Urea/Carbamates FAAH MAGL Or Dual FAAH/MAGL Inhibitors And Uses Thereof

ABSTRACT

Disclosed are compounds that may be used to inhibit the action of fatty acid amide hydrolase (FAAH), monoacylgly-cerol lipase (MAGL) or dual FAAH/MAGL.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/328,428, filed Jan. 23, 2017, which is the U.S. National Stage ofInternational Application No. PCT/US2015/042055, filed Jul. 24, 2015,published in English, which claims the benefit of U.S. ProvisionalApplication No. 62/029,006, filed Jul. 25, 2014, the contents of whichare hereby incorporated by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under Grant NumberDA007215 awarded by the National Institutes of Health, and Grant NumberDE-FG02-00ER45852 awarded by the Department of Energy. The governmenthas certain rights in the invention.

FIELD OF THE INVENTION

The present disclosure relates generally to ureas and carbamates thatinhibit FAAG, MAGL or dual FAAH/MAGL, and to the manufacture thereof anduses thereof. For example, the compounds can be used for treating pain,inflammation, neuropathy, neurodegenerative disease, anxiety disorder,motor function disorder, fertility disorder, appetite disorder,THC-dependence, metabolic disorder, movement disorder, and chemotherapyinduced nausea and vomiting (CINV) and cancer.

BACKGROUND

Presently, two G_(i/o) protein coupled cannabinoid receptors have beencharacterized in mammals and other organism (Devane et al., Brain Mol.Pharmacol. (1988) 34: 605-613, Matsuda et al., Nature (1990) 346:561-564). Cannabinoid receptor 1(CB1) is a central receptor found in themammalian brain and a number of other sites in peripheral tissues; andCB2, a peripheral receptor found principally in cells related to theimmune system. Cannabinergic ligands can bind to the CB1 and/or CB2receptors in an individual or animal. In vitro methods for assaying theability of a compound to bind to CB1 and/or CB2 receptors are known(Devane et al., Brain Mol. Pharmacol. (1988) 34: 605-613). Results fromthe in vitro assay correlate with and predict the in vivo ability ofthat compound to bind to CB1 and/or CB2 receptors and modulate theirfunction(s).

When introduced in an individual or animal some of these cannabinergicligands can bind to and directly modulate (activate or deactivate) theCB1 and/or CB2 receptors. Many physiological effects have beenassociated with direct modulation of the CB1 and/or CB2 receptors in anindividual or animal (Jonsson et al. Basic and Clinical Pharmacol.Toxic. (2006) 98: 124-134), Examples of cannabinergic ligands include(−)-Δ⁹-tetrahydrocannabinol ((−)-Δ⁹-THC), the principal bioactiveconstituent of cannabis and exogenous ligand for the cannabinoid CB1 andCB2 receptors) and other synthetic cannabinergic analogs. The majorendogenous ligands for the CB receptors are N-arachidonoyl ethanolamine(anandamide, AEA) and 2-arachidonoylglycerol (2-AG) (Devane et al,Science (1992) 258: 1946-1949, Mechoulam et al Biochem. Pharmacol.(1995) 50: 83-90).

The magnitude and duration of in vivo CB1 and/or CB2 receptor modulationby endocannabinoids AEA and 2-AG is relatively short, presumably due torapid inactivation process involving endocannabinoid deactivatingproteins. Anandamide for example, is inactivated via fatty acid amidehydrolase (FAAH) mediated hydrolysis (Deutsch et al. Biochem. Pharmacol.1993, 46, 791-796). FAAH belongs to the amidase signature (AS) superfamily of serine hydrolases and in contrast to the classicalserine-histidine-aspartate triad found in most serine hydrolases, thecatalytic machinery of this enzyme is a serine-serine-lysine catalytictriad. FAAH has been isolated, molecularly cloned and its 2.8 Å crystalstructure was recently reported. 2-arachidonoylglycerol (2-AG),1-arachidonoylglycerol, arachidonamide and the corresponding simpleester methyl arachidonate are also substrates for FAAH.

Moreover, studies have demonstrated that this enzyme not only canhydrolyze anandamide into arachidonic acid and ethanolamine it can alsocatalyze reverse synthesis from the two hydrolysis components. Alsonotable is FAAH's ability to hydrolyze several bioactive fatty acidamides not belonging to the endocannabinoid family, for example, thesleep inducing lipid oleamide, the appetite-suppressing agentoleoylethanolamine, the related 1-oleoylglycerol, and the peripheralanalgesic and anti-inflammatory mediator palmitoylethanolamine. Despitethe fact that a range of fatty acid amides, ethanolamides and esters arehydrolyzed by FAAH, this enzyme appears to work most effectively onarachidonoyl and oleoyl substrates.

Although FAAH has been shown to also catalyze hydrolysis of2-arachidonoylglycerol in vitro, a distinct enzyme, monoacylglycerollipase (MAGL,) plays the predominant role in catalyzing 2-AG (the mostabundant endocannabinoid) hydrolysis in vivo (Karlsson et al J. Biol.Chem. (1997) 272: 27218-27223). Monoacylglycerol lipase, also known asMAGL, MAG lipase or MAGL is a serine hydrolase that is also notable forits ability to hydrolyze several bioactive fatty acid glyceryl estersnot belonging to the endocannabinoid family, for example,2-oleoylglycerol and 2-palmitoyl glycerol. MAGL plays dual roles inphysiologic processes, encompassing regulating endocannabinoid tone aswell as lipogenesis (Dinh et al Proceedings of the National Academy ofSciences of the United States of America (2002) 99: 10819; Schlosburg etal Nature neuroscience (2010) 13: 1113. Site-directed mutagenesisstudies (Zvonok et al Chemistry & biology (2008) 15: 854; Zvonok et alJournal of Proteome Research (2008) 7: 2158) as well as X-ray crystalstructure of a complex with its ligand have identified the enzyme'scatalytic triad as Ser¹²²-Asp²³⁹-His²⁶⁹ (Labar et al Chembiochem: aEuropean journal of chemical biology (2010) 11: 218; Schalk-Hihi et alProtein science: a publication of the Protein Society (2011) 20: 670.

Some compounds can inhibit the inactivation of cannabinergic ligands byFAAH, by MAGL, or by dual FAAH/MAGL. These compounds may not bind to, ormay have lesser affinity for, the cannabinoid receptors. Thus, thephysiological action for such compounds is inhibition of fatty acidamide hydrolase (FAAH) and not direct modulation of the CB1 and/or CB2receptors. The inactivation of endocannabinoids by FAAH, MAGL, or dualFAAH/MAGL can be inhibited. These inhibitors may not bind to, or mayhave lesser affinity for, the cannabinoid receptors. Thus, thephysiological action for such compounds is inhibition of FAAH and orMAGL and not direct modulation of the CB1 and/or CB2 receptors.Inhibition of FAAH, MAGL, or dual FAAH/MAGL in an individual or animalwill slow the normal degradation and inactivation of endogenouscannabinoid ligands by FAAH or MAGL hydrolysis and allow higher levelsof those endogenous cannabinergic ligands to remain present in thatindividual or animal. These higher levels of endocannabinoid induceincreased stimulation of the cannabinoid CB1 and CB2 receptors andproduce physiological effects related to the activation of thecannabinoid receptors. They will also enhance the effects of otherexogenous cannabinergic ligands and allow them to produce their effectsat lower concentrations as compared to systems in which FAAH, MAGL, ordual FAAH/MAGL action is not inhibited. Thus, a compound that inhibitsthe inactivation of endogenous cannabinoid ligands by FAAH, MAGL, ordual FAAH/MAGL may increase the levels of endocannabinoids and, thus,enhance the activation of cannabinoid receptors. The compound may notdirectly modulate the cannabinoid receptors but has the effect ofindirectly stimulating the cannabinoid receptors by increasing the invivo levels of endocannabinoid ligands. It may also enhance the effectsand duration of action of other exogenous cannabinergic ligands that areadministered in order to elicit a cannabinergic response.

Marijuana-like cannabinoids, in addition to acting at cannabinoidreceptors also affect cellular membranes, thereby producing undesirableside effects such as drowsiness, impairment of monoamide oxidasefunction and impairment of non-receptor mediated brain function. Theaddictive and psychotropic properties of some cannabinoids also limittheir therapeutic value. Compounds that inhibit FAAH, MAGL, or dualFAAH/MAGL activity may indirectly provide desirable pharmacologicalproperties while avoiding the disadvantages incurred by use ofcannabinergic ligands that directly activate the cannabinoid receptors.Compounds that inhibit FAAH and or MAGL activity provide an alternativemechanism for indirectly stimulating cannabinoid receptors and mayprovide desirable pharmacological properties without the addictive andpsychotropic properties as well as other undesirable propertiesassociated with exogenous cannabinergic ligands.

FAAH, MAGL, or dual FAAH/MAGL inhibitory compounds comprise twopharmacophoric subunits responsible for enzyme recognition andinactivation. The “inhibition” subunit typically comprises an activatedcarbonyl group and the “binding” subunit, which is linked to theinhibition subunit, enhances the inhibitory action of the molecule.

Conditions that may be treated by modulation of the CB1/CB2 cannabinoidreceptors include for example: high blood pressure disease orhypertension; peripheral vascular diseases; coronary artery disease;abnormal heart rate; pulmonary hypertension; ocular hypertension orglaucoma; tumor growth; to prevent or reduce inflammation; to provideneuroprotection; to treat epilepsy; to treat nausea, such as associatedwith cancer chemotherapy; AIDS wasting syndrome as well as otherailments in which cannabinoid system is implicated.

SUMMARY OF THE INVENTION

The present disclosure relates to compounds of general formulas I-III toinhibit FAAH, MAGL or dual FAAH/MAGL, their methods of preparation anduses thereof. In some embodiments the compounds are FAAH inhibitors. Inother embodiments the compounds comprise MAGL inhibitors and in furtherembodiments the compounds comprise dual FAAH/MAGL inhibitors. Someaspects of the present disclosure provide use of compounds of generalformulas I-III to inhibit FAAH, MAGL or dual FAAH/MAGL.

The disclosures of the present application include methods for indirectmodulation of cannabinoid receptors, and methods for treating variousdisorders in a subject. One aspect of the application is directed to amethod of modulating cannabinoid receptors in a biological sample. Inthis method, the level of a cannabinergic ligand in the biologicalsample is measured. Then, the biological sample is contacted withcompounds of formulas I-III. The level of the cannabinergic ligand inthe contacted sample is then measured, to determine if the level of thecannabinergic ligand in the contacted sample is the same or greater thanthe level of the cannabinergic ligand in the uncontacted sample.

In a particular embodiment, the enzyme inhibited by compounds offormulas I-III is FAAH and the cannabinergic ligand is anadamide. Inanother embodiment, the enzyme inhibited is MAGL and the cannabinergicligand is 2-arachidonoylglycerol (2-AG). In a further certainembodiment, the enzymes inhibited are dual FAAH and MAGL and thecannabinergic ligands are anadamide and 2-AG. In some embodiments,effects of modulating CB1/CB2 receptors are assessed.

Inhibition of FAAH, MAGL or dual FAAH/MAGL will slow the normaldegradation and inactivation of endogenous cannabinoid ligands by FAAH,MAGL or dual FAAH/MAGL hydrolysis and allow higher levels of endogenousanadamide and 2-arachidonoylglycerol to remain present. These higherlevels of endocannabinoid ligands provide increased stimulation of thecannabinoid CB1 and CB2 receptors and produce physiological effectsrelated to the activation of the cannabinoid receptors. Compounds offormulas I-III will also enhance the effects of other exogenouscannabinergic ligands (e.g. Δ⁹-THC) and allow them to produce effects atlower concentrations as compared to systems in which FAAH, MAGL or dualFAAH/MAGL action is not inhibited. The compound may not directlymodulate the cannabinoid receptors but has the effect of indirectlystimulating the cannabinoid receptors by increasing the levels ofendocannabinoid ligands. FAAH, MAGL or dual FAAH/MAGL inhibition inducesCB1, CB2 or dual CB1/CB2-dependent beneficial effects that may be usedto prevent or reduce inflammation; to provide neuroprotection; treatTHC-dependence; to treat cancer; to treat chemotherapy induced nauseaand vomiting (CINV) associated with cancer chemotherapy; to treat AIDSwasting syndrome as well as other ailments in which cannabinoid systemis implicated.

A further aspect of the invention is directed to treating certaindisorders in a subject e.g., neuropathic pain. The method comprisesadministering a therapeutically effective amount of a compound offormula I, II or III to the subject. The administration of the compoundtreats the neuropathy of the subject. In some embodiments the neuropathyis neuropathic pain, diabetic neuropathy, neuropathy caused bychemotherapeutic agents, central pain, peripheral pain, pellargicneuropathy, alcoholic neuropathy, beriberi neuropathy, burning painsyndrome. In yet other embodiments, the neuropathy is aneurodegenerative disease. In particular embodiments, theneurodegenerative disease is multiple sclerosis, Parkinson's disease,Huntington's chorea, Alzheimer's disease, amyotrophic lateral sclerosis,

In particular embodiments, the invention is directed to treating mooddisorder, sleep disorder, gastrointestinal motility disorder, irritablebowel syndrome, diarrhea, cardiovascular disease, hypertension,osteoporosis, osteoarthritis, emesis, epilepsy, a mental disorder,schizophrenia, depression, glaucoma, cachexia, insomnia, traumatic braininjury, spinal cord injury, seizures, excitotoxin exposure, ischemia, orAIDS wasting syndrome.

An additional aspect of the application is directed to a method oftreating a motor function disorder in a subject. In particularembodiment the motor function disorder is Tourette's syndrome. Themethod comprises administering to the subject a therapeuticallyeffective amount of a compound of formula I, II or III. Theadministration of the compound treats the motor function disorder of thesubject. An additional aspect of the disclosure is directed to a methodof treating a fertility disorder in a subject. The method comprisesadministering to the subject a therapeutically effective amount of acompound of formula I, II or III. The administration of the compoundtreats the fertility disorder of the subject.

Another aspect of the application is directed to a method of treating ananxiety disorder in a subject. The method comprises administering to thesubject a therapeutically effective amount of a compound of formula I,II or III. The administration of the compound treats the anxietydisorder of the subject. In certain embodiments, the anxiety disorder ispanic disorder, acute stress disorder, post-traumatic stress disorder,substance-induced anxiety disorder, obsessive compulsive disorder,agoraphobia, specific phobia, or social phobia.

In yet another aspect, the disclosure is directed to a method oftreating an appetite disorder in a subject. The method comprisesadministering to the subject a therapeutically effective amount of acompound of formula I, II or III. The administration of the compoundtreats the appetite disorder of the subject.

In another embodiment administration of the compound treats themetabolic disorder in a subject. The method comprises administering tothe subject a therapeutically effective amount of a compound of formulaI, II or III. The administration of the compound treats the metabolicdisorder of the subject.

In still another aspect, the disclosure is directed to a method oftreating movement disorder in a subject. The method comprisesadministering to the subject a therapeutically effective amount of acompound of formula I, II or III. The administration of the compoundtreats the movement disorder of the subject. Another aspect of thedisclosure is directed to a method of treating cancer in a subject. Themethod comprises administering to the subject a therapeuticallyeffective amount of a compound of formula I, II or III. Theadministration of the compound treats the cancer of the subject. Afurther aspect of the invention is directed to treating nausea inducedby chemotherapy

The method comprises administering to the subject a therapeuticallyeffective amount of a compound of formula I, II or III. Theadministration of the compound treats nausea induced by chemotherapy ofthe subject.

Compounds of formula I-III can affect endocannabinoid levels in the CNSby inhibiting FAAH and or MAGL activities. In addition to these centralmechanisms, peripheral FAAH and or MAGL can also be inhibited.Administration of compounds that are restricted to the peripheraltissues can selectively inhibit FAAH and or MAGL in these tissues. Someof the compounds in this disclosure can selectively inhibit FAAH and orMAGL in peripheral system.

DETAILED DESCRIPTION Compounds

This invention relates to compounds of Formulas I-III

In a particular embodiment this invention relates to compounds ofFormula I

wherein

X=CH, N; M=O, S;

Z=O, NH, or none, when Z is none B1 is directly attached to C=M;R1=—H, -alkyl;R2=—H, -alkyl, where alkyl is saturated C1-10 hydrocarbon, which may bestraight or branched chain;L1 is selected from —(CH2)n-, —O(CH2)n-, —O—, —SO2-, —C(═O)—, when X isN, or —(CH2)n-, —(CH2)nO-, —O—, —CH═CH—, —CONH—, —S—, —S(═O)—, —SO2-,—NH—, —NR1- when X is CH, where n=0-6;A1 is selected from aryl, heteroaryl, benzhydryl, fluorenyl,aryl(aryl)methyl, aryl(phenyl)methyl, aryl(alkyl)methyl,aryl(cycloalkyl)methyl and each aryl, heteroaryl or fluorenyl group maybe unsubstituted, mono or di-substituted with following moieties;—NO2, —CN, —OH, -alkyl, —O-alkyl, -halogen, —CF3, —OCF3, —S-alkyl, —OPh,-Ph, —S(O)— alkyl, —SO2-alkyl, —CO2-alkyl, —COOH, —NHR3, —NR3R4,—NR3SO2R4, —NO2, —CN, —CONR3R4; morpholino; thiomorpholino,1,1-dioxothiomorpholine, oxothiomorpholino,R3 and R4 are independently selected from —H or -alkyl, cycloalkyl;

B₁ can be selected from aryl, heteroaryl, and each aryl or heteroarylgroup may be unsubstituted or substituted at a carbon ring member withone or two moieties as defined below;

halogen —NO₂, —CN, —OH, —NH₂, —CONH₂, —O-aryl, —CF₃, —OCF₃, —OCF₂H,—SCF₃, —OPh;

where n, m=1-3;Q₁ is selected from CO, —CH(OH), O, S, S(O), SO₂;R₅ is selected from H, OH, halogen,R₆ is selected from H, —CN, —OH, —OMe, —CF₃, —OCF₃, —OBn, —CONH₂,—SO₂NH₂, —COOH;B1 also encompasses:

where Ar can be aryl or heteroaryl containing 1 to 3 heteroatoms;W1 is either CH or N;

W2 is —CH2, —CH—Ar or —N—Ar;

R7 is selected from monocyclic heteroaryl ring containing 1 to 3heteroatoms and each aryl or hetroaryl ring can be substituted with oneor two groups as defined below:halogen —NO₂, —CN, —OH, —NH₂, —CONH₂, —O-aryl, —CF₃, —OCF₃, —OCF₂H,—SCF₃, —OPh; R₈ is selected from —H, —OH, -halogen.

Particularly useful compounds of Formula I include those compoundswherein: L₁ is selected from —(CH₂)_(n)—, —O(CH₂)_(n)—, —(CH₂)_(n)O—,—SO₂—, —C(═O)—, when X is N, or —(CH₂)_(n)—, (CH₂)_(n)O—, —O—, —CH═CH—,—CONH—, —S—, —S(═O)—, —SO₂—, —NH—, —NR₁— when X is CH, where n=0-3, moreparticularly where n=0-2;

The following compounds of Formula I are also particularly useful,wherein:

M=O;

L₁ is selected from —(CH₂)_(n)—, —SO₂, —C(═O)—, when X is N, or—(CH₂)_(n)O—, O, S, —S(O)—, SO₂, when X is CH, where n=0-2;

A₁ is selected from aryl, heteroaryl, benzhydryl, fluorenyl,aryl(aryl)methyl, aryl(phenyl)methyl, aryl(alkyl)methyl,aryl(cycloalkyl)methyl and each aryl, heteroaryl or fluorenyl group maybe unsubstituted, mono or di-substituted with following moieties;-alkyl, —O-alkyl, -halogen, —CF₃, —OPh, -Ph, morpholino; thiomorpholino,1,1-dioxothiomorpholine;

B₁ can be selected from aryl, heteroaryl, and each aryl or heteroarylgroup may be unsubstituted or substituted at a carbon ring member withone or two moieties as defined below;

—H, -halogen —CN, —OH, —OMc, —CONH2, —CF3;

Where n, m=2; and Q1 is SO2;R6 is selected from —H, -halogen —CN, —OH, —OMe, —CONH2, —CF3;B₁ also encompasses:

and the other substituents are the same as set forth above.

In accordance with another aspect, the present invention relates tocompounds of formula IA

wherein

X=CH, N;

R₁=—H, -alkyl;R₂=—H, -alkyl, where alkyl is saturated C₁₋₁₀ hydrocarbon, which may bestraight or branched chain;n=0-3;A₁ is selected from aryl, heteroaryl, benzhydryl, fluorenyl,aryl(aryl)methyl, aryl(phenyl)methyl, aryl(alkyl)methyl,aryl(cycloalkyl)methyl and each aryl, heteroaryl or fluorenyl group maybe unsubstituted, mono or di-substituted with following moieties:—NO₂, —CN, —OH, -alkyl, —O-alkyl, -halogen, —CF₃, —OCF₃, —S-alkyl, —OPh,-Ph, —S(O)-alkyl, —SO₂-alkyl, —CO₂-alkyl, —COOH, —NHR₃, —NR₃R₄,—NR₃SO₂R₄, —NO₂, —CN, —CONR₃R₄; morpholino; thiomorpholino,1,1-dioxothiomorpholine, oxothiomorpholino,R₃ and R₄ are independently selected from —H or alkyl, cycloalkyl; andR₆ is selected from H, —CN, —OH, —OMe, —CF₃, —OCF₃, —OBn, —CONH₂,—SO₂NH₂, —COOH.

In accordance with particular embodiments, the compounds of Formula IAare those in which

X=N and n=0-1. In accordance with certain embodiments, R₆ is selectedfrom —H, —CN, —CONH₂, —CF₃. In accordance with particularly usefulembodiments, A₁ is selected from the group consisting of: phenoxyphenyl,quinolinyl, phenyl, fluorenyl, pyridinyl, and biphenyl.

In accordance with another aspect, the present invention relates tocompounds of formula IB

whereinR₁=—H, -alkyl;R₂=—H, -alkyl, where alkyl is saturated C₁₋₁₀ hydrocarbon, which may bestraight or branched chain;L₁ is selected from a double bond, —(CH₂)_(n)—, —O—, —CH═CH—, —CONH—,—S—, —S(═O)—, —SO₂—, —NH—, —NR₁—, where n=0-6;

A₁ is selected from aryl, heteroaryl, benzhydryl, fluorenyl,aryl(aryl)methyl, aryl(phenyl)methyl, aryl(alkyl)methyl,aryl(cycloalkyl)methyl and each aryl, heteroaryl or fluorenyl group maybe unsubstituted, mono or di-substituted with following moieties;

—NO₂, —CN, —OH, -alkyl, —O-alkyl, -halogen, —CF₃, —OCF₃, —S-alkyl, —OPh,-Ph —S(O)-alkyl, —SO₂-alkyl, —CO₂-alkyl, —COOH, —NHR₃, —NR₃R₄,—NR₃SO₂R₄, —NO₂, —CN, —CONR₃R₄; morpholino; thiomorpholino,1,1-dioxothiomorpholine, oxothiomorpholino,R₃ and R₄ are independently selected from —H or -alkyl, -cycloalkyl;R₅ is selected from —H, —OH, halogen,R₆ is selected from —H, —CN, —OH, —OMe, —CF₃, —OCF₃, —OBn, —CONH₂,—SO₂NH₂, —COOH.

In certain embodiments, L₁ is selected from a double bond and —(CH₂)n-and n=0-1. In accordance with some embodiments, R₅ is selected from —H,halogen; and R₆ is selected from —H, —CN, —CONH₂, —CF₃. In accordancewith particularly useful compounds, A₁ is selected from the groupconsisting of: phenyl, benzyl and benzhydryl.

Examples of certain useful compounds of Formula I include:

-   Example 1:    (S)—N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-3-methyl-4-(quinolin-2-ylmethyl)    piperazine-1-carboxamide-   Example 2:    (R)—N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-3-methyl-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide-   Example 3:    (S)—N-(3′-cyano-[1,1′-biphenyl]-3-yl)-2-methyl-4-(3-phenoxybenzyl)piperazine-1-carboxamide-   Example 4:    (S)—N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-2-methyl-4-(3-phenoxybenzyl)piperazine-1-carboxamide-   Example 5:    (S)—N-(5-(3-cyanophenyl)pyridin-3-yl)-2-methyl-4-(3-phenoxybenzyl)piperazine-1-carboxamide-   Example 6:    N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-(quinolin-3-ylmethyl)piperazine-1-carboxamide-   Example 7:    N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-phenylpiperidine-1-carboxamide-   Example 8:    N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-(9H-fluoren-9-yl)piperazine-1-carboxamide-   Example 9:    N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-(pyridin-2-yl)piperazine-1-carboxamide-   Example 10:    4-([1,1′-biphenyl]-4-ylmethyl)-N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)piperazine-1-carboxamide-   Example 11:    N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-phenylpiperazine-1-carboxamide-   Example 12:    N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide-   Example 13:    N-(3′-cyano-[1,1′-biphenyl]-3-yl)-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide-   Example 14:    N-(3-phenoxyphenyl)-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide-   Example 15:    N-(3′-cyano-[1,1′-biphenyl]-3-yl)-4-phenylpiperidine-1-carboxamide-   Example 16:    N-(5-(3-cyanophenyl)pyridin-3-yl)-4-phenylpiperidine-1-carboxamide-   Example 17:    4-([1,1′-biphenyl]-3-ylmethyl)-N-(3′-cyano-[1,1′-biphenyl]-3-yl)piperazine-1-carboxamide-   Example 18:    N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-(3-phenoxybenzyl)piperazine-1-carboxamide-   Example 19:    (S)—N-(3′-cyano-[1,1′-biphenyl]-3-yl)-3-methyl-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide-   Example 20:    N-(3′-cyano-[1,1′-biphenyl]-3-yl)-4-oxospiro[chromane-2,4′-piperidine]-1′-carboxamide-   Example 21:    (S)-(4-([1,1′-biphenyl]-3-ylmethyl)-3-methylpiperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone-   Example 22:    (S)-(4-bromo-1H-imidazol-1-yl)(2-methyl-4-(3-phenoxybenzyl)piperazin-1-yl)methanone-   Example 23:    (2-methyl-4-phenylpiperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone-   Example 24:    (3-methyl-4-phenylpiperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone-   Example 25:    (3-methyl-4-(p-tolyl)piperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone-   Example 26:    (4-(3-(benzyloxy)phenyl)-3-methylpiperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone-   Example 27:    (4-(3-hydroxyphenyl)-3-methylpiperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone-   Example 28:    (4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)(4-bromo-1H-imidazol-1-yl)methanone-   Example 29:    (4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone-   Example 30:    (4-benzhydrylpiperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone-   Example 31:    (4-benzhydrylpiperazin-1-yl)(5-benzyl-1H-tetrazol-1-yl)methanone-   Example 32:    (5-benzyl-1H-tetrazol-1-yl)(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)methanone-   Example 33:    (3-(Carbomethoxy)-1H-1,2,4-triazol-1-yl)(4-(bis(4-fluorophenyl)methyoxy)pipe-ridin-1    yl)methanone-   Example 34:    4′-(4-bromo-1H-imidazole-1-carbonyl)spiro[chromane-2,1′-cyclohexan]-4-one-   Example 35: 3-Cyanophenyl    4-(2-methyl-1-phenylpropyl)piperazine-1-carboxylate-   Example 36: 3-cyanophenyl 4-(1-phenylethyl)piperazine-1-carboxylate-   Example 37: 3-cyanophenyl    4-(cyclopentyl(phenyl)methyl)piperazine-1-carboxylate-   Example 38: 3-cyano-5-hydroxyphenyl    4-benzhydrylpiperazine-1-carboxylate-   Example 39: 6-chloropyridin-2-yl    4-benzhydrylpiperazine-1-carboxylate-   Example 40: 3-cyanophenyl    4-(bis(4-fluorophenyl)methyl)piperazine-1-carboxylate-   Example 41: 3-cyanophenyl    4-(9H-fluoren-9-yl)piperazine-1-carboxylate-   Example 42: 4-cyanopyridin-2-yl    4-(9H-fluoren-9-yl)piperazine-1-carboxylate-   Example 43: 3-cyanopyridin-2-yl    4-(9H-fluoren-9-yl)piperazine-1-carboxylate-   Example 44: 3-Cyanophenyl 4-benzhydrylpiperazine-1-carboxylate-   Example 45: 5-Cyano-2-fluorophenyl 4-benzylpiperidine-1-carboxylate-   Example 46: 3-Cyanophenyl 4-benzhydrylpiperidine-1-carboxylate-   Example 47: 3-cyanophenyl    4-(diphenylmethylene)piperidine-1-carboxylate-   Example 48: 3-(methoxycarbonyl)phenyl    4-(diphenylmethylene)piperidine-1-carboxylate-   Example 49: 5-cyano-2-fluorophenyl    4-benzhydrylpiperidine-1-carboxylate-   Example 50: 3-cyano-5-hydroxyphenyl    4-benzhydrylpiperidine-1-carboxylate-   Example 51: 6-Chloropyridin-2-yl    4-(benzhydryl)piperidine-1-carboxylate-   Example 52: 3-cyanophenyl 4-benzylpiperidine-1-carboxylate-   Example 53: 3-cyanophenyl    4-((4-chlorophenyl)(2-chloropyridin-3-yl)methoxy)piperidine-1-carboxylate-   Example 54 6-Chloropyridin-2-yl    4-(benzhydryl)piperidine-1-carboxylate-   Example 55: 3-(methoxycarbonyl)phenyl    4-(benzhydryloxy)piperidine-1-carboxylate-   Example 56: 5-cyano-2-fluorophenyl    4-(benzhydryloxy)piperidine-1-carboxylate-   Example 57: 6-chloropyridin-2-yl    4-(benzhydryloxy)piperidine-1-carboxylate-   Example 58: 3-cyanophenyl 4-(benzhydryloxy)piperidine-1-carboxylate-   Example 59: 3-Cyanophenyl    4-(4-bromophenylsulfonyl)piperidine-1-carboxylate-   Example 60: 5-Cyano-2-fluorophenyl    4-(4-bromophenylsulfonyl)piperidine-1-carboxylate-   Example 61: 5-Cyano-2-methylphenyl    4-(4-bromophenylsulfonyl)piperidine-1-carboxylate-   Example 62: 5-Cyano-2-methoxyyphenyl    4-(4-bromophenylsulfonyl)piperidine-1-carboxylate-   Example 63: 2,6-Difluorophenyl    4-(4-bromophenylsulfonyl)piperidine-1-carboxylate-   Example 64: 4-bromophenyl 4-tosylpiperazine-1-carboxylate-   Example 65: 2,6-difluorophenyl 4-tosylpiperazine-1-carboxylate-   Example 66: 4′-fluoro-3-hydroxy-[1,1′-biphenyl]-4-yl    4-tosylpiperazine-1-carboxylate-   Example 67:    N-(3-(1,1-dioxidothiomorpholino)phenyl)-4-phenylpiperazine-1-carboxamide-   Example 68:    N-(3-(1,1-dioxidothiomorpholino)phenyl)-4-phenylpiperidine-1-carboxamide-   Example 69: 3-(1,1-dioxidothiomorpholino)phenyl    4-phenylpiperazine-1-carboxylate-   Example 70: 3-(1,1-Dioxothiomorpholin-4-yl)phenyl    4-phenylpiperidine-1-carboxylate-   Example 71: 3-(1,1-dioxidothiomorpholino)phenyl    4-(3-phenoxybenzyl)piperazine-1-carboxylate-   Example 72: 3-(1,1-dioxidothiomorpholino)phenyl    4-(quinolin-2-ylmethyl)piperazine-1-carboxylate-   Example 73: 3-(1,1-dioxidothiomorpholino)phenyl    2-methyl-4-phenylpiperazine-1-carboxylate

In another embodiment, this invention relates to compounds of Formula II

Wherein M=O, S;

Z=O, NH, or none; when Z=none B₂ is directly attaches to C=M;n=1-2L₂ is selected from

—O—, —CH═CH—, —CONH,

—S—, —S(O)—, SO₂, —NH—, n=0-2, more particularly n=0-1;

A₂ is selected from aryl, heteroaryl, fluoren-9-yl, aryl(alkyl)methyl,aryl(cycloalkyl)methyl, heteroaryl(alkyl)methyl, orheteroaryl(cycloalkyl)methyl and each aryl, heteroaryl or fluore-9-nylgroup may be unsubstituted, or substituted with one or two moieties asdefined below;

—OH, -alkyl, —O-alkyl, -halogen, —CF₃, —OCF₃, —S-alkyl, —OPh, -Ph—S(O)-alkyl, —SO₂-alkyl, —CO₂-alkyl, —COOH, —NHR, —NR₃R₄, —NR₃SO₂R₄,—NO₂, —CN, —CONR₃R₄, -alkynyl, morpholino, thiomorpholino,1,1-dioxothiomorpholine, 1-oxothiomorpholino;R₃ and R₄ are independently selected from —H or -alkyl, cycloalkyl;

B₂ can be selected from aryl or heteroaryl groups, and each aryl orheteroaryl group may be unsubstituted or substituted with one or twomoieties as defined below:

-halogen —NO₂, —CN, —OH, —NH₂, —CONH₂, —O-aryl, —CF₃, —OCF₃, —OCF₂H,—SCF₃;B₂ is also encompassing

wherein W₁ is either CH or N;W₂ is selected from CH₂, O, SO₂, CHAr, or NAr;Ar can be aryl or heteroaryl containing 1 to 3 heteroatoms;R₅ is selected from —H, -halogen —NO₂, —CN, —OH, -Ph, —COOMe; —NH₂,—CONH₂, —O-aryl, —CF₃, —OCF₃, —OCF₂H, —SCF₃;R₆ is selected from monocyclic heteroaryl ring containing 1 to 3heteroatoms, and the heteroaryl ring can be substituted with one or twogroups, as defined below:—CN, —OH, —OMe, —CF₃, —OCF₃, —OBn, —CONH₂, —SO₂NH₂, —COOH -halogen, orwherein M can be selected from O or S,

Particularly useful compounds of Formula II include those compoundswherein Z=O, NH, or none; when Z=none B₃ is directly attaches to C=M;

n=1-2; and the remaining substituents are as described above.

Still more particularly useful compounds of Formula II include thosecompounds wherein

M=O;

L₂ is selected A₂-(CH₂)O—, —O—, —S—, —S(O)—, SO₂, —NH—, n=0-1;

A₂ is selected from aryl, heteroaryl, and each aryl, heteroaryl groupmay be unsubstituted, or substituted with one or two moieties as definedbelow:

-halogen;

B₂ can be selected from aryl or heteroaryl groups, and each aryl orheteroaryl group may be unsubstituted or substituted with one or twomoieties as defined below:

-halogen —CN, —CONH₂, —CF₃;B₂ also encompasses:

R₅ is selected from —H, -Ph, —COOMe; R₅R₆ is selected from monocyclic heteroaryl ring containing 1 to 3heteroatoms, and the heteroaryl ring can be substituted with one or twogroups, as defined below:halogen.

Examples of particularly useful compounds of Formula II include:

-   Example 74 3-Cyanophenyl    3-(4-chlorobenzyloxy)azetidine-1-carboxylate-   Example 75: 3-(Trifluoromethyl)phenyl    3-(4-chlorobenzyloxy)azetidine-1-carboxylate-   Example 76: 3-Bromophenyl    3-(4-chlorobenzyloxy)azetidine-1-carboxylate-   Example 77: 3-Carbamoylphenyl    3-(4-chlorobenzyloxy)azetidine-1-carboxylate-   Example 78: 3-Methoxyphenyl    3-(4-Bromobenzyloxy)azetidine-1-carboxylate-   Example 79: 2,4-Dichlorophenyl    3-(4-chlorobenzyloxy)azetidine-1-carboxylate-   Example 80: 3-(Pyridin-3-yl)phenyl    3-(4-chlorobenzyloxy)azetidine-1-carboxylate-   Example 81 3-(4-Chlorobenzyloxy)-N-phenylazetidine-1-carboxamide-   Example 82:    3-(4-Bromobenzyloxy)-N-(pyridin-3-yl)azetidine-1-carboxamide-   Example 83    (1H-Benzo[d]imidazol-1-yl)(3-(4-phenylpiperidin-1-yl)azetidin-1-yl)methanone-   Example 84    (3-(4-Benzylpiperidine)azetidin-1-yl)(4-phenyl[1H]imizadol-1-yl)methanone-   Example 85    (4-Phenyl-1H-imidazol-1-yl)(3-(4-phenylpiperidin-1-yl)azetidin-1-yl)methanone-   Example 86    (3-(4-Bromobenzyloxy)azetidin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone-   Example 87    (1H-Benzo[d]imidazol-1-yl)(3-(4-Bromobenzyloxy)azetidin-1-yl)methanone-   Example 88    3-(4-Bromobenzyloxy)azetidin-1-yl](piperidin-1-yl)methanone-   Example 89    (3-(4-Phenylpiperidin-1-yl)azetidin-1-yl)(1H-pyrazol-1-yl)methanone-   Example 90    3-(4-Phenylpiperidin-1-yl)azetidin-1l-yl)(1H-1,2,4-triazol-1-yl)methanone-   Example 91    3-(4-Bromophenylthio)azetidin-1-yl)(1H-1,2,4-triazol-1-yl)methanone.

In a another embodiment, this invention relates to compounds of FormulaIII

Wherein X=CH, N; M=O, S;

Z=O, NH, or none; when Z=none, B₃ directly attaches to C=M;n=1-3L₃ is selected from —(CH₂)_(n),

—C(═O)— when X is N, or from —(CH₂)_(n)O—, —O—, —CH═CH—, —CONH—, —NH—,—NR₁ when X is CH, where n=0-3;

A₃ is selected from aryl, heteroaryl, fluoren-9-yl, and each aryl,heteroaryl or fluoren-9-yl group may be unsubstituted, or substitutedwith one or two moieties as defined below;

-halogen —NO₂, —CN, —OH, —NH₂, —CONH₂, —CO₂Me; -alkyl, —Oalkyl,-halogen, —CF₃, —OCF₃, —Salkyl, —OCH₂Ph, -Ph, —S(O)-alkyl, —SO₂-alkyl,—CO₂-alkyl, —COOH, —NHR₃, —NR₃R₄, —NR₃SO₂R₄, —NO₂, —CN, —CONR₃R₄;morpholino; thiomorpholino, 1,1-dioxothiomorpholine, oxothiomorpholino;R₃ and R₄ are independently selected from —H or -alkyl, cycloalkyl;

B₃ can be selected from aryl or heteroaryl groups, and each aryl orheteroaryl group may be unsubstituted or substituted with one or twomoieties as defined below:

—H, -halogen, —CN, —OH, —NH₂, —CO₂Me, —CONH₂, —OMe;

B₃ is also encompassing

Wherein W₁ is either CH or N;Ar can be aryl or heteroaryl containing 1 to 3 heteroatoms;R₅ is selected from —H, -halogen, —CN, —OH, —NH₂, —CO₂Me, —CONH₂, —OMe;R₆ is selected from monocyclic heteroaryl ring containing 1 to 3heteroatoms, and the heteroaryl ring can be substituted with one or twogroups as defined below,—CN, —OH, —OMe, —CF₃, —OCF₃, —OCH₂Ph, —CONH₂, —SO₂NH₂, —COOH, halogen or

Wherein M can be selected from O or S,

Particularly useful compounds of Formula III include those compoundswherein L₃ is selected from —(CH₂)_(n), or —C(═O)— when X is N, or L₃ isselected from —(CH₂)_(n)O—, —O—, —CH═CH—, —CONH—, —NH—,

—NR₁ when X is CH, where n=0-2;

B₃ can be selected from aryl or heteroaryl groups, and each aryl orheteroaryl group may be unsubstituted or substituted with one or twomoieties as defined below:

-halogen, —CN, —OH, —CO₂Me, —CONH₂;

B₃ is also encompassing and the remaining substituents are as describedabove.

More particularly useful compounds of Formula III are those compoundswherein

X=N; M=O;

Z=O, NH or none; when Z=none B₃ is directly attaches to C=M;n=1L₃ is selected from is selected from —(CH₂)n where n is 0 or 1;

A₃ is selected from aryl, heteroaryl, fluorenyl, and each aryl,heteroaryl group may be unsubstituted, substituted with one or twomoieties as defined below;

-halogen, —OCH₂Ph, -Ph;

B₃ can be selected from aryl or heteroaryl groups, and each aryl orheteroaryl group may be unsubstituted or substituted with moieties asdefined below:

—CN, —CO₂Me, —CONH₂;

B₃ can be

R₆ is selected from H, halogen, or Phenyl and the remaining substituentsare as set forth above.

Examples of compounds of Formula III include:

-   Example 92:    (1S,4S)—N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-5-(quinolin-2-ylmethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide-   Example 93:    (1S,4S)—N-(3′-cyano-[1,1′-biphenyl]-3-yl)-5-(quinolin-2-ylmethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide-   Example 94:    (1S,4S)-5-([1,1′-biphenyl]-3-ylmethyl)-N-(3′-cyano-[1,1′-biphenyl]-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide-   Example 95:    (1S,4S)—N-(3-bromophenyl)-5-(quinolin-2-ylmethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide-   Example 96:    (4-phenyl-1H-imidazol-1-yl)((1S,4S)-5-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methanone-   Example 97: ((1    S,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(4-phenyl-1H-imidazol-1-yl)methanone-   Example 98:    ((1S,4S)-5-(3-(benzyloxy)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(4-phenyl-1H-imidazol-1-yl)methanone-   Example 99:    ((1S,4S)-5-([1,1′-biphenyl]-3-ylmethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(4-phenyl-1H-imidazol-1-yl)methanone-   Example 100:    ((1S,4S)-5-([1,1′-biphenyl]-3-ylmethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(4-bromo-1H-imidazol-1-yl)methanone-   Example 101: phenyl    (1S,4S)-5-([1,1′-biphenyl]-3-ylmethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Definitions

The compounds of this disclosure include any and all possible isomers,stereoisomers, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, and solvates thereof. Thus, the terms“compound” and “compounds” as used in this disclosure refer to thecompounds of this disclosure and any and all possible isomers,stereoisomers, enantiomers, diastereomers, tantomers,pharmaceutically-acceptable salts, and solvates thereof. In general, thecompositions of the disclosure can be alternately formulated tocomprise, consist of, or consist essentially of, any appropriatecomponents disclosed in this application. The compositions of thedisclosure can additionally, or alternatively, be formulated so as to bedevoid, or substantially free, of any components, materials,ingredients, adjuvants or species used in the prior art compositions orthat are otherwise not necessary to the achievement of the functionand/or objectives of the present disclosure. Reference to compounds ofFormula I-II includes subsets thereof (e.g. Formula IA).

For convenience, certain terms employed in the specification, examplesand claims are collected here. Unless defined otherwise, all technicaland scientific terms used in this disclosure have the same meanings ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs. The initial definition provided for a group or termprovided in this disclosure applies to that group or term throughout thepresent disclosure individually or as part of another group, unlessotherwise indicated.

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “or” is used in this disclosure to mean, and is usedinterchangeably with, the term “and/or,” unless indicated otherwise.

The term “about” is used in this disclosure to mean a value − or +20% ofa given numerical value. Thus, “about 60%” means a value between 60-20%of 60 and 60+20% of 60 (i.e., between 48% and 72%).

Unless otherwise specifically defined, “alcohol” refers to the generalformula alkyl-OH and includes primary, secondary and tertiaryvariations.

Unless otherwise specifically defined, the term “alkyl” refers tooptionally unsubstituted or substituted straight or branched chainhydrocarbon radical containing from 1 to 10 carbon atoms. Examples ofsuch groups include, but are not limited to methyl, ethyl, n-propyl,i-propyl, n-butyl, sec-butyl, tert-butyl etc.

Unless otherwise specifically defined, the term “cycloalkyl” refers to afully saturated cyclic hydrocarbon group containing from 3-10 carbonatoms in a cycloalkyl ring. Examples of such groups include, but are notlimited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, adamantyl, etc. Unless otherwise specifically defined, theterm “adamantyl” includes, but is not limited to, 1-adamantyl,2-adamantyl, and 3-adamantyl, etc.

Unless otherwise specifically defined, the term “alkenyl” refers to astraight or branched chain hydrocarbon radical containing from 2 to 15carbon atoms and at least one carbon-carbon double bond. Exemplary suchgroups include, but are not limited to, ethenyl (also called “vinyl”),allyl, propenyl, crotyl, 2-isopentenyl, allenyl, butenyl, butadienyl,pentenyl, pentadienyl, 3(1,4-pentadienyl), hexenyl and hexadienyl. Thealkenyl group may be optionally substituted with one or moresubstituents, e.g., 1 to 5 substituents, at any available point ofattachment. Exemplary substituents include, but are not limited to,alkyl or substituted alkyl, as well as those groups recited above asexemplary alkyl substituents. The exemplary substituents can themselvesbe optionally substituted.

Unless otherwise specifically defined, the term “alkynyl” refers to astraight or branched chain hydrocarbon radical containing from 2 to 15carbon atoms and at least one carbon-carbon triple bond. Exemplary suchgroups include, but are not limited to, ethynyl, propynyl and butynyl.The alkynyl group may be optionally substituted with one or moresubstituents, e.g., 1 to 5 substituents, at any available point ofattachment. Exemplary substituents include, but are not limited to,alkyl or substituted alkyl, as well as those groups recited above asexemplary alkyl substituents. The exemplary substituents can themselvesbe optionally substituted.

Unless otherwise specifically defined, “aryl” refers to aryl groups (orrings) that contain only carbon atoms. Aryl group (or aryl ring) includephenyl, naphthyl, anthracene, phenathrene etc.

Unless otherwise specifically defined, “heteroaryl” refers to arylgroups (or rings) that contain one or more heteroatoms selected fromoxygen, nitrogen and/or sulfur as ring atoms. Heteroaryl groups (orrings) also include fused polycyclic systems in which one or moremonocyclic aryl or monocyclic heteroaryl group is fused to anotherheteroaryl group. “Heteroaryl” can include “divalent radicals”, the term“divalent heteroaryl radicals” unless otherwise specifically definedrefers to the general formula: -heteroaryl-. Examples of heteroarylgroups include but are not limited to, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, imidazolyl, oxadiazolyl,pyridinyl, pyrimidinyl, purinyl, benzoxazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, indolyl, quinolinyl, quinoxalinyl.

Unless otherwise specifically defined, “halogen” refers to an atomselected from fluorine, chlorine, bromine and iodine.

The phrase “pharmaceutically acceptable” is employed in this disclosureto refer to those compounds, materials, compositions, and/or dosageforms which are, within the scope of sound medical judgment, suitablefor use in contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

The term “salt(s)”, as employed in this disclosure, denotes acidicand/or basic salts formed with inorganic and/or organic acids and bases.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating can be curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The terms “effective amount” and “therapeutically effective amount” asused in this disclosure refer to an amount of a compound that, whenadministered to a subject, is capable of reducing a symptom of adisorder in a subject. The actual amount which comprises the “effectiveamount” or “therapeutically effective amount” will vary depending on anumber of conditions including, but not limited to, the particulardisorder being treated, the severity of the disorder, the size andhealth of the patient, and the route of administration. A skilledmedical practitioner can readily determine the appropriate amount usingmethods known in the medical arts.

As used in this disclosure, the term “subject” includes, withoutlimitation, a human or an animal Exemplary animals include, but are notlimited to, mammals such as mouse, rat, guinea pig, dog, cat, horse,cow, pig, monkey, chimpanzee, baboon, or rhesus monkey.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a compound orpharmaceutically acceptable salt of the compound or a composition to asubject, or administering a pro-drug derivative or analog of thecompound or pharmaceutically acceptable salt of the compound orcomposition to the subject, which can form an equivalent amount ofactive compound within the subject's body. The compounds of the presentinvention may be converted to salts in particular pharmaceuticallyacceptable salts using art recognized procedures.

Compounds of the invention may be prepared employing conventionalmethods that utilize readily available reagents and starting materials.The inhibitory compounds need not be made exclusively from theillustrative syntheses. A person of skill in the art understands thatadditional methods of making the inhibitory compounds exist. A person ofskill in the art also understands that general synthetic schemes for thecompounds disclosed herein can be understood from the illustrativeschemes below.

Methods of Inhibition and Modulation

This disclosure is also directed to a method of assessing the modulatingeffect on cannabinoid receptors in a biological sample by using thecompounds of Formulas I-III and their pharmaceutically acceptable saltsthereof. The method comprises (a) measuring the level of a cannabinergicligand in the biological sample, (b) contacting the sample with acompound of Formula I, II, or III, thereby inhibiting an enzyme thathydrolyzes the cannabinergic ligand, and (c) measuring the level of thecannabinergic ligand in the contacted sample, the cannabinoid receptorsbeing modulated if the level of the cannabinergic ligand in thecontacted sample is the same or greater than the level of thecannabinergic ligand in the uncontacted sample.

In some instances, the enzyme inhibited is FAAH and in other examplesMAGL is inactivated. In further examples testing of some compounds ofFormulas I-III shows inhibition of FAAH/MAGL in both in vitro and invivo systems. Inhibition of FAAH, MAGL, or dual FAAH/MAGL has the effectof preventing the degradation of endocannabinoid ligands and increasingor maintaining the level of endocannabinoid ligands in a system. Thus,the disclosed compounds, when administered in a therapeuticallyeffective amount, increase or maintain the in vivo concentration ofendogenous cannabinergic ligands in a subject, thereby enhancing ormaintaining activation of cannabinoid receptors. In other instances, theinhibitor also inhibits FAAH in addition to MAGL. The joint inactivationof both enzymes leads to enhanced therapeutic benefits becausecannabinoid receptors can be modulated by additional cannabinergicligands.

Methods of Treating Disorders Using FAAH and or MAGL InhibitoryCompounds

Some of the physiological effects provided by modulation of thecannabinoid receptors by cannabinergic ligands are useful to treat adisorder in a subject. Such treatable physiological effects include, butare not limited to, neuroprotection; reduction of inflammation;reduction of pain; reduction of central pain; reduction of peripheralpain; modulation of memory; sleep inducement; modulation of the immunesystem; hypotension; reduction of emesis; effects on gastrointestinalmotility; effects on motor function; effects on intestinal transit andcolonic propulsion; modulation of appetite; and modulation of fertility.Inhibition of FAAH and or MAGL activity increases or maintains theconcentration of existing levels of endogenous cannabinergic ligands andthereby increases or maintains the magnitude and duration of thephysiological effect provided by those cannabinergic ligands. Therefore,the disclosed compounds, and therapeutic formulations containing suchcompounds, enhance or maintain the magnitude and duration of thephysiological effects produced by a cannabinergic ligand in a subjectwhen administered in therapeutically effective amounts.

Disorders that can be treated by inhibition of MAGL and/or MAGL and FAAHand indirect stimulation of the cannabinoid receptors include, forexample: appetite disorders, metabolic disorders, movement disorders,inflammation, pain, neuropathic pain (e.g., neuropathic low back pain,complex regional pain syndrome, post trigeminal neuralgia, causalgia,toxic neuropathy, reflex sympathetic dystrophy, diabetic neuropathy,chronic neuropathy caused by chemotherapeutic agents), central pain,peripheral pain, neuropathy (e.g., diabetic neuropathy, pellagricneuropathy, alcoholic neuropathy, Beriberi neuropathy, burning feetsyndrome), neurodegenerative diseases including multiple sclerosis,Parkinson's disease, Huntington's chorea, Alzheimer's disease,amyotrophic lateral sclerosis; memory disorders, mood disorders, sleepdisorders, gastrointestinal motility disorders such as irritable bowelsyndrome and diarrhea; cardiovascular disease, hypertension,osteoporosis, osteoarthritis, emesis, epilepsy, mental disorders such asschizophrenia and depression; glaucoma, cachexia, insomnia, traumaticbrain injury, spinal cord injury, seizures, excitotoxin exposure,ischemia, AIDS wasting syndrome, psychological disorders includinganxiety disorders (e.g., panic disorder, acute stress disorder,post-traumatic stress disorder, substance-induced anxiety disorders,obsessive-compulsive disorder, agoraphobia, specific phobia, socialphobia), to modulate the immune system; to regulate fertility; toprevent or reduce diseases associated with motor function such asTourette's syndrome; to provide neuroprotection, to produce peripheralvasodilation; to slow down intestinal transit and colonic propulsion; totreat several types of cancer, as well as other ailments in which agrowing family of bioactive lipid mediators is implicated.

The disclosed inhibitory compounds and pharmaceutical formulations canalso be used in combination with one or more agents treating and/ortargeting the disorder or the endogenous cannabinergic system. Suchagents include, but are not limited to, CB1 cannabinoid receptoragonists, CB2 cannabinoid receptor agonists, analgesics, FAAHinhibitors, anadamide transport inhibitors, COX-2 enzyme inhibitors,anxiolytics, antidepressants, and opioids. For example, these compoundsand pharmaceutical formulations can be used in conjunction with othercannabinergic ligands that act directly on the CB1 and CB2 receptors.

In certain instances, the cannabinergic ligand is2-arachidonoylglycerol. The disclosed compounds have high potential tobe used as research tools to probe MAGL and related lipase mechanisms ofcatalysis, and to uncover the biological roles of lipid mediators suchas 2-arachidonoylglycerol. For example, the disclosed compounds can beused as in vivo imaging agents; to maintain the level of2-arachidonoylglycerol in vitro to study the effect of2-arachidonoylglycerol in cells and to enhance the levels of2-arachidonoylglycerol in vivo in order to study the effect of2-arachidonoylglycerol on humans and animals. The disclosed compoundscan be used to characterize cells, for example, to determine if a celltype has cannabimimetic or lipase activity. For example, the disclosedcompounds can be used to determine if a cell population expresses MAGLby contacting the cells with a disclosed compound and then determiningif there is an increase in the concentration of 2-arachidonoylglycerol.The inhibitors disclosed in this application can also be used as an aidin drug design, for example as a control in assays for testing othercompounds for their ability to inhibit MAGL and to determine thestructure activity requirements of MAGL inhibitors.

The disclosed compounds can also be used to prepare prodrugs. Prodrugsare known to those skilled in the art of pharmaceutical chemistry, andprovide benefits such as increased adsorption and half-life. Thoseskilled in the art of drug delivery will readily appreciate that thepharmacokinetic properties of Formula (I) can be controlled by anappropriate choice of moieties to produce prodrug derivatives.

Formulation

This disclosure is also directed to a pharmaceutical formulationcomprising at least one compound of Formula I, II or III, and apharmaceutically-acceptable carrier. Such formulations are suitable foradministration to a subject. The pharmaceutical formulation can be usedfor treating a disorder described above.

Any suitable pharmaceutically acceptable carrier known in the art can beused as long as it does not affect the inhibitory activity of a compoundof Formula I, II or III. Carriers may be used that efficientlysolubilize the agents. Carriers include, but are not limited to, asolid, liquid, or a mixture of a solid and a liquid. The carriers cantake the form of capsules, tablets, pills, powders, lozenges,suspensions, emulsions, or syrups. The carriers can include substancesthat act as flavoring agents, lubricants, solubilizers, suspendingagents, binders, stabilizers, tablet disintegrating agents, andencapsulating materials. Other examples of suitable physiologicallyacceptable carriers are described in Remington's Pharmaceutical Sciences(21st ed. 2005), incorporated into this disclosure by reference.

Non-limiting examples of materials which can serve aspharmaceutically-acceptable carriers include: (1) sugars, such aslactose, glucose, and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline, (18) Ringer'ssolution, (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

The formulations can conveniently be presented in unit dosage form andcan be prepared by any methods known in the art of pharmacy. The amountof compound of Formula (I) which can be combined with a carrier materialto produce a single-dosage form will vary depending upon the subjectbeing treated, the particular mode of administration, the particularcondition being treated, among others. The amount of active ingredientthat can be combined with a carrier material to produce a single-dosageform will generally be that amount of the compound that produces atherapeutic effect. Generally, out of one hundred percent, this amountwill range from about 1 percent to about ninety-nine percent of activeingredient, in some instances from about 5 percent to about 70 percent,in other instances from about 10 percent to about 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound disclosed in this applicationwith a carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of Formula (I-III) with liquidcarriers, or timely divided solid carriers, or both, and then, ifnecessary, shaping the product.

In solid dosage forms of the disclosed compounds for oral administration(e.g., capsules, tablets, pills, dragees, powders, granules, and thelike), the active ingredient is mixed with one or more additionalingredients, such as sodium citrate or dicalcium phosphate, and/or anyof the following: (1) fillers or extenders, such as, but not limited to,starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2)binders, such as, but not limited to, carboxymethylcellulose, alginates,gelatin, polyvinyl pyrrolidone, sucrose, and/or acacia; (3) humectants,such as, but not limited to, glycerol; (4) disintegrating agents, suchas, but not limited to, agar, calcium carbonate, potato or tapiocastarch, alginic acid, certain silicates, and sodium carbonate; (5)solution retarding agents, such as, but not limited to, paraffin; (6)absorption accelerators, such as, but not limited to, quaternaryammonium compounds; (7) wetting agents, such as, but not limited to,cetyl alcohol and glycerol monostearate; (8) absorbents, such as, butnot limited to, kaolin and bentonite clay; (9) lubricants, such as, butnot limited to, talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and(10) coloring agents. In the case of capsules, tablets, and pills, thepharmaceutical compositions can also comprise buffering agents. Solidcompositions of a similar type can also be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugars, as well as high molecular weight polyethylene glycols, andthe like.

In powders, the carrier is a finely-divided solid, which is mixed withan effective amount of a finely-divided agent. Powders and sprays cancontain, in addition to a compound of Formula (I-III), excipients, suchas lactose, talc, silicic acid, aluminum hydroxide, calcium silicatesand polyamide powder, or mixtures of these substances. Sprays canadditionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

Tablets for systemic oral administration can include one or moreexcipients as known in the art, such as, for example, calcium carbonate,sodium carbonate, sugars (e.g., lactose, sucrose, mannitol, sorbitol),celluloses (e.g., methyl cellulose, sodium carboxymethyl cellulose),gums (e.g., arabic, tragacanth), together with one or moredisintegrating agents (e.g., maize, starch, or alginic acid, bindingagents, such as, for example, gelatin, collagen, or acacia), lubricatingagents (e.g., magnesium stearate, stearic acid, or talc), inertdiluents, preservatives, disintegrants (e.g., sodium starch glycolate),surface-active and/or dispersing agent. A tablet can be made bycompression or molding, optionally with one or more accessoryingredients.

In solutions, suspensions, emulsions or syrups, an effective amount of adisclosed compound is dissolved or suspended in a carrier, such assterile water or an organic solvent, such as aqueous propylene glycol.Other compositions can be made by dispersing the agent in an aqueousstarch or sodium carboxymethyl cellulose solution or suitable oil knownto the art. The liquid dosage forms can contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as, but not limited to, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils(in particular, cottonseed, groundnut, corn, germ, olive, castor andsesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols,and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also includeadjuvants, such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, coloring, perfuming, and preservative agents.Suspensions can contain, in addition to the active compound, suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

Formulations of the pharmaceutical compositions for rectal or vaginaladministration can be presented as a suppository, which can be preparedby mixing one or more compounds of this disclosure with one or moresuitable non-irritating excipients or carriers comprising, for example,cocoa butter, polyethylene glycol, a suppository wax or a salicylate,and which is solid at RT but liquid at body temperature and, thus, willmelt in the rectum or vaginal cavity and release the agents.Formulations suitable for vaginal administration also include, but arenot limited to, pessaries, tampons, creams, gels, pastes, foams, orspray formulations containing such carriers as are known in the art tobe appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this disclosure include, but are not limited to, powders, sprays,ointments, pastes, creams, lotions, gels, solutions, patches, andinhalants. The active compound can be mixed under sterile conditionswith a pharmaceutically-acceptable carrier, and with any preservatives,buffers, or propellants.

Ointments, pastes, creams, and gels can contain, in addition to anactive compound, excipients, such as animal and vegetable fats, oils,waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of Formula (I) to the body. Such dosage forms canbe made by dissolving or dispersing the agents in the proper medium.Absorption enhancers can also be used to increase the flux of the agentsacross the skin. The rate of such flux can be controlled by eitherproviding a rate controlling membrane or dispersing the compound in apolymer matrix or gel.

The compounds of Formulas I-III are administered in a therapeuticallyeffective amount to a patient in need of such treatment. Such an amountis effective in treating a disorder of the patient. This amount canvary, depending on the activity of the agent utilized, the nature of thedisorder, and the health of the patient. A skilled practitioner willappreciate that the therapeutically-effective amount of a compound ofFormula I, II or III can be lowered or increased by fine-tuning and/orby administering more than one compound of Formulas I-III, or byadministering a compound of Formula I, II or III together with a secondagent (e.g., antibiotics, antifungals, antivirals, NSAIDS, DMARDS,steroids, etc.). Therapeutically-effective amounts can be easilydetermined, for example, empirically by starting at relatively lowamounts and by step-wise increments with concurrent evaluation ofbeneficial effect (e.g., reduction in symptoms). The actual effectiveamount will be established by dose/response assays using methodsstandard in the art (Johnson et al., Diabetes., (1993) 42:1179). As isknown to those in the art, the effective amount will depend onbioavailability, bioactivity, and biodegradability of the compound ofFormula I, II or III.

A therapeutically-effective amount is an amount that is capable ofreducing a symptom of a disorder in a subject. Accordingly, the amountwill vary with the subject being treated. Administration of the compoundof Formula I, II or III can be hourly, daily, weekly, monthly, yearly,or a single event. For example, the effective amount of the compound cancomprise from about 1 μg/kg body weight to about 100 mg/kg body weight.In one embodiment, the effective amount of the compound comprises fromabout 1 μg/kg body weight to about 50 mg/kg body weight. In a furtherembodiment, the effective amount of the compound comprises from about 10μg/kg body weight to about 10 mg/kg body weight. When one or morecompounds of Formulas I-III or agents are combined with a carrier, theycan be present in an amount of about 1 weight percent to about 99 weightpercent, the remainder being composed of the pharmaceutically-acceptablecarrier.

Administration

Methods of administration of the therapeutic formulations comprising thecompounds of Formulas I-III can be by any of a number of methods knownin the art. These methods include, but are not limited to, local orsystemic administration. Exemplary routes of administration include, butare not limited to, oral, parenteral, transdermal, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal(e.g., nebulizer, inhaler, aerosol dispenser), colorectal, rectal,intravaginal, and any combinations thereof. In addition, it may bedesirable to introduce pharmaceutical compositions of the disclosedcompounds into the central nervous system by any suitable route,including intraventricular and intrathecal injection. Intraventricularinjection can be facilitated by an intraventricular catheter, forexample, attached to a reservoir, such as an Ommaya reservoir. Methodsof introduction can be provided by rechargeable or biodegradabledevices, e.g., depots. Furthermore, administration can occur by coatinga device, implant, stent, or prosthetic. The compounds of Formulas I-IIIcan also be used to coat catheters in any situation where catheters areinserted in the body.

The therapeutic formulations containing a compound of Formula I, II orIII can also be administered as part of a combinatorial therapy withother agents. Combination therapy refers to any form of administrationcombining two or more different therapeutic compounds such that thesecond compound is administered while the previously administeredtherapeutic compound is still effective in the body (e.g., the twocompounds are simultaneously effective in the patient, which may includesynergistic effects of the two compounds). For example, the differenttherapeutic compounds can be administered either in the same formulationor in a separate formulation, either simultaneously or sequentially.Thus, an individual who receives such treatment can have a combined(conjoint) effect of different therapeutic compounds.

In other instances, for example, in the case of inflammatory conditions,a therapeutic formulation containing a compound of Formula I, II or IIIcan be administered in combination with one or more other agents usefulin the treatment of inflammatory diseases or conditions. Agents usefulin the treatment of inflammatory diseases or conditions include, but arenot limited to, anti-inflammatory agents, or antiphlogistics. Exemplaryantiphlogistics include, but are not limited to, glucocorticoids, suchas cortisone, hydrocortisone, prednisone, prednisolone, fluorcortolone,triamcinolone, methylprednisolone, prednylidene, paramethasone,dexamethasone, betamethasone, beclomethasone, fluprednylidene,desoxymethasone, fluocinolone, flunethasone, diflucortolone,clocortolone, clobetasol and fluocortin butyl ester; immunosuppressiveagents such as anti-TNF agents (e.g., etanercept, infliximab) and IL-1inhibitors; penicillamine; non-steroidal anti-inflammatory drugs(NSAIDs) which encompass anti-inflammatory, analgesic, and antipyreticdrugs such as salicyclic acid, celecoxib, difunisal and from substitutedphenylacetic acid salts or 2-phenylpropionic acid salts, such asalclofenac, ibutenac, ibuprofen, clindanac, fenclorac, ketoprofen,fenoprofen, indoprofen, fenclofenac, diclofenac, flurbiprofen, piprofen,naproxen, benoxaprofen, carprofen and cicloprofen; oxican derivatives,such as piroxican; anthranilic acid derivatives, such as mefenamic acid,flufenamic acid, tolfenamic acid and meclofenamic acid,anilino-substituted nicotinic acid derivatives, such as the fenamatesmiflumic acid, clonixin and flunixin; heteroarylacetic acids whereinheteroaryl is a 2-indol-3-yl or pyrrol-2-yl group, such as indomethacin,oxmetacin, intrazol, acemetazin, cinmetacin, zomepirac, tolmetin,colpirac and tiaprofenic acid; idenylacetic acid of the sulindac type;analgesically active heteroaryloxyacetic acids, such as benzadac;phenylbutazone; etodolac; nabunetone; and disease modifyingantirheumatic drugs (DMARDs) such as methotrexate, gold salts,hydroxychloroquine, sulfasalazine, ciclosporin, azathioprine, andleflunomide. Other therapeutics useful in the treatment of inflammatorydiseases or conditions include antioxidants. Antioxidants can be naturalor synthetic. Antioxidants are, for example, superoxide dismutase (SOD),21-aminosteroids/aminochromans, vitamin C or E, etc. Many otherantioxidants are known to those of skill in the art. The compounds ofFormula (I) can serve as part of a treatment regimen for an inflammatorycondition, which may combine many different anti-inflammatory agents.For example, the subject compounds can be administered in combinationwith one or more of an NSAID, DMARD, or immunosuppressant. The subjectcompounds can also be administered in combination with methotrexate. Thesubject antibodies can also be administered in combination with a TNF-αinhibitor.

In the case of cardiovascular disease conditions, and particularly thosearising from atherosclerotic plaques, which are thought to have asubstantial inflammatory component, the therapeutic formulationincluding a compound of Formula (I) can be administered in combinationwith one or more other agents useful in the treatment of cardiovasculardiseases. Agents useful in the treatment of cardiovascular diseasesinclude, but are not limited to, β-blockers such as carvedilol,metoprolol, bucindolol, bisoprolol, atenolol, propranolol, nadolol,timolol, pindolol, and labetalol; antiplatelet agents such as aspirinand ticlopidine; inhibitors of angiotensin-converting enzyme (ACE) suchas captopril, enalapril, lisinopril, benazopril, fosinopril, quinapril,ramipril, spirapril, and moexipril; and lipid-lowering agents such asmevastatin, lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, and rosuvastatin.

In the case of cancer, the subject compounds can be administered incombination with one or more anti-angiogenic factors, chemotherapeutics,or as an adjuvant to radiotherapy. It is further envisioned that theadministration of the subject compounds will serve as part of a cancertreatment regimen, which may combine many different cancer therapeuticagents.

The disclosure is further illustrated by the following examples, whichare not to be construed as limiting this disclosure in scope or spiritto the specific procedures described in this disclosure. It is to beunderstood that the examples are provided to illustrate certainembodiments and that no limitation to the scope of the disclosure isintended thereby. It is to be further understood that resort may be hadto various other embodiments, modifications, and equivalents thereofwhich may suggest themselves to those skilled in the art withoutdeparting from the sprint of the present disclosure and/or scope of theappended claims.

FAAH Inhibitory Compounds

Certain chemical compounds have been found to inhibit the inactivationof endocannabinoids by FAAH. These compounds may not bind to, or mayhave lesser affinity for, the CB1 and/or CB2 cannabinoid receptors.Thus, the physiological action for such compounds and may not be thedirect modulation of the CB1 and/or CB2 receptors. Inhibition of FAAH ina subject slows the normal degradation and inactivation of AEA and otherfatty acid amides. This inhibition allows maintained or higher levels ofthose endogenous ligands to remain present in the subject. Themaintained or higher levels of those ligands provide increasedstimulation of the cannabinoid CB 1 and CB2 receptors. The inhibition ofFAAH also enhances the effects of exogenous cannabinergic ligands andallows them to stimulate cannabinoid receptors at lower concentrationsas compared to systems in which FAAH action is not inhibited.

MAGL Inhibitory Compounds

Certain chemical compounds have been found to inhibit the inactivationof endocannabinoids by MAGL. These compounds may not bind to, or mayhave lesser affinity for, the CB1 and/or CB2 cannabinoid receptors.Thus, the physiological action for such compounds and may not be thedirect modulation of the CB1 and/or CB2 receptors. Inhibition of MAGL ina subject slows the normal degradation and inactivation of 2-AG andother 2-monoacylglycerols (2-MAGs). This inhibition allows maintained orhigher levels of those endogenous ligands to remain present in thesubject. The maintained or higher levels of those ligands provideincreased stimulation of the cannabinoid CB1 and CB2 receptors.

Dual FAAH/MAGL Inhibitory Compounds

Certain chemical compounds have been found to inhibit the inactivationof endocannabinoids by FAAH/MAGL. These compounds may not bind to, ormay have lesser affinity for, the CB1 and/or CB2 cannabinoid receptors.Thus, the physiological action for such compounds and may not be thedirect modulation of the CB1 and/or CB2 receptors. Inhibition ofFAAH/MAGL in a subject slows the normal degradation and inactivation ofanandamide and other fatty acid ethanolamines as well as 2-AG and other2-monoacylglycerols (2-MAGs). This inhibition allows maintained orhigher levels of those endogenous ligands to remain present in thesubject. The maintained or higher levels of those ligands provideincreased stimulation of the cannabinoid CB1 and CB2 receptors.

Example processes for synthesis of compounds of Formula I-III areprovided below in Methods A-M:

The inhibitory compounds of Formula I-III can be synthesized by chemicalmeans as described in methods A-M below. Novel compounds may besynthesized from commercially available starting material. Theinhibitory compounds need not be made exclusively from the illustrativesyntheses. A person of skill in the art understands that additionalmethods of making the inhibitory compounds exist. A person of skill inthe art also understands that general synthetic schemes for thecompounds disclosed herein can be understood from the illustrativeschemes below

Method A: Synthesis of N-Aryl Urea Derivatives 7

Referring to Scheme I, N-Aryl urea derivatives 7 were synthesized byreaction of piperazine derivatives 3 with substituted biaryl phenylcarbamates 6, under microwave irradiation. Piperazine derivatives 3 wereobtained by deprotection of N-BOC group 2 under acidic condition. Arylpiperazine derivatives 2 (n=: 0) were obtained by Buchwald coupling (Xieet al, J. Org. Chem., (2006) 71: 6522-6529) of aryl bromides or iodideswith substituted N-BOC piperazines 1. Aryl piperazine derivatives 2(n=1) were produced by nucleophilic displacement of benzyl chlorides orbenzyl bromides with commercially available substituted N-BOCpiperazines 1 The common intermediate biaryl phenyl carbamates 6 weresynthesized by Suzuki coupling (Bermejo et al, J. Am. Chem. Soc., (2008)130: 15798-15799) of aryl boronic acids 4 with nm-bromoaniline to givebiaryl amine derivatives 5, which were further treated with phenylchloroformate to give phenyl carbamates 6, as shown in scheme I.

The Following Examples were Prepared by Following Method A

Synthesis of Example 1(S)—N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-3-methyl-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide (7; A₁=Quinoline, n=1, R₁=3-Me, R₂=H, R₃=CONH₂)Step a) Synthesis of Tert-butyl(S)-3-methyl-4-(quinolin-2-ylmethyl)piperazine-1-carboxylate

A solution of 2-(chloromethyl)quinoline hydrobromide (2.0 g, 7.74 mmol)in acetonitrile (20 mL) was added tert-butyl(S)-2-methylpiperazine-1-carboxylate 1, (1.86 g, 9.28 mmol) andtriethylamine (1.61 mL, 11.61 mmol) and the resulting mixture was heatedin a sealed tube under microwave irradiation at 100° C. for 15 min withstirring. The reaction mixture was cooled to room temperature. Thesolvent was removed in vacuo and the residue partitioned betweendichloromethane and water. The aqueous layer was further extracted withdichloromethane and the combined organic extracts were washed withbrine, and dried over MgSO₄. The solvent was removed in vacuo to give acrude product, which was purified by flash column chromatography to give2.25 g of tert-butyl(S)-3-methyl-4-(quinolin-2-ylmethyl)piperazine-1-carboxylate.

¹H NMR (500 M Hz, CDCl₃) δ 8.13 (d, 1H, J=9 Hz); 8.06 (d, 1H, J=9.0 Hz);7.81 (d, 1H, J=8.0 Hz); 7-71-7.66 (m, 2H); 7.51 (t, 1H, J=8.0 Hz); 8.13(bd, 1H, J=9.0 Hz) 8.06 (bd, 1H, J=9.0 Hz); 4.25 (d, 1H, J=14 Hz);3.84-3.65 (m, 3H); 3.15 (bs, 1H); 2.93 (bs, 1H); 2.70 (bs, 1H); 2.58(bs, 1H); 0.96 (bs, 9H)

Step c) Synthesis of (S)-2-((2-methylpiperazin-1-yl)methyl)quinolone

To a solution of tert-butyl(S)-3-methyl-4-(quinolin-2-ylmethyl)piperazine-1-carboxylate 2 (2.0 g,5.86 mmol) in methylene chloride (25 mL) was added trifluoroacetic acid(2.25 mL, 29.3 mmol). After stirring at room temperature for 16 h, themixture was concentrated in vacuo, and diluted with ethyl acetate andaqueous sodium bicarbonate. The organic layer was washed with brine,dried over MgSO₄ and concentrated, to give product(S)-2-((2-methylpiperazin-1-yl)methyl)quinolone (1.27 g) which wasfurther used at the next step without any purification.

¹H NMR (500 M Hz, CDCl₃) δ 8.13 (d, 1H, J=9 Hz); 8.06 (d, 1H, J=9.0 Hz);7.81 (d, 1H, J=8.0 Hz); 7-71-7.66 (m, 2H); 7.51 (t, 1H, J=8.0 Hz); 8.13(bd, 1H, J=9.0 Hz) 8.06 (bd, 1H, J=9.0 Hz); 4.25 (d, 1H, J=14 Hz);3.84-3.65 (m, 3H); 3.15 (bs, 1H); 2.93 (bs, 1H); 2.70 (bs, 1H); 2.58(bs, 1H

Step d) Synthesis of 3′-amino-[1,1′-biphenyl]-3-carboxamide

A mixture of 3-bromo aniline (1.0 g, 5.81 mmol),(3-carbamoylphenyl)boronic acid (1.25 g, 7.56 mmol) (4), Ba(OH)₂ (2.75g, 8.72 mmol), and Pd(PPh₃)₄ (80 mg) in DME (3 mL)/water (2 mL) wasflushed with argon, and heated in a sealed tube under microwaveirradiation at 120° C. for 15 min with stirring. The reaction mixturewas cooled to room temperature, diluted with EtOAc (20 mL) and aqueousNH₄Cl solution. the catalyst was removed by filtration through a celitepad. The organic layer was washed with water, brine, and dried overMgSO₄, and concentrated under vacuo. Purification by flash columnchromatography gave 0.96 g of 3′-amino-[1,1′-biphenyl]-3-carboxamide, aswhite solid.

¹H NMR (500 M Hz, CDCl₃) δ 8.04 (d, 2H, J=7.5 Hz); 7.63-7.47 (m, 3H);7.32 (d, 1H, J=6.0 Hz); 3.93 (s, 2H); 2.65 (t, 4H, J=5.5 Hz); 2.34 (t,4H, J=5.5 Hz)

Step e) Synthesis of Phenyl (3′-carbamoyl-[1,1′-biphenyl]-3-yl)carbamate

To a solution of 3′-amino-[1,1′-biphenyl]-3-carboxamide (2.0 g, 9.42mmol) in dry THF (30 mL) at 0° C., was added phenyl chloroformate (1.63g, 10.4 mmol) drop wise over 15 min period. The reaction mixture wasallowed to warm to room temperature. After 12 h, the mixture was dilutedwith EtOAc (100 mL) and washed with aqueous NaHCO₃ solution (20 mL). Theorganic layer was dried over MgSO₄ and concentrated. The residue waschromatographed to give 2.72 g of phenyl(3′-carbamoyl-[1,1′-biphenyl]-3-yl)carbamates as a white solid.

¹H NMR (500 M Hz, CDCl₃) δ 9.29 (bs, 1H); 8.22 (s, 1H); 7.98 (s, 1H);7.98 (d, 1H, J=8 Hz); 7.82 (d, 1H, J=8 Hz); 7.66 (d, 1H, J=8 Hz); 7.56(t, 2H, J=8 Hz); 7.49-7.41 (m, 3H); 7.27-7.23 (m, 2H)

Step f) Synthesis of(S)—N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-3-methyl-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide ((7; A₁=Quinoline, n=1, R₁=3-Me, R₂=H,R₃=CONH₂)

A solution of (S)-2-((2-methylpiperazin-1-yl)methyl)quinolone (0.6 g,2.64 mmol) and biphenyl-3-yl-carbamic acid phenyl ester 6 (0.92 g, 2.77mmol) in acetonitrile (10 mL) was heated in a scaled tube undermicrowave irradiation at 120° C. for 10 min with stirring. The reactionmixture was cooled to room temperature and solvent was removed underreduced pressure. The crude material was partitioned betweendichloromethane and water. The aqueous phase was extracted withdichloromethane. The combined extracts were dried over MgSO₄ andconcentrated. The residue was chromatographed to give 1.03 g of(S)—N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-3-methyl-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide, as a white solid.

¹H NMR (500 M Hz, CDCl₃) δ 8.16 (d, 1H, J=7 Hz); 8.02 (d, 1H, J=7 Hz);8.01 (s, 1H); 7.81 (d, 1H, J=7 Hz); 7.68-7.73 (m, 3H); 7.65 (d, 1H, J=5Hz); 7.58-7.52 (m, 2H); 7.41-7.46 (m, 2H); 7.32 (t, 1H, J=7.5 Hz); 7.21(d, 1H, J=7.5 Hz); 6.99 (s, 1H); 6.45 (bs, 1H); 6.48 (bs, 1H); 4.24 (d,1H, J=12 Hz); 3.86 (d, 1H, J=13 Hz); 3.74 (td, 1H, J=12.5 Hz); 3.63 (d,1H, J=14 Hz); 3.24 (td, 1H, J=10 Hz, J=3 Hz); 3.03 (dd, 1H, J=13 Hz, J=9Hz); 2.77 (dt, 1H, J=12 Hz, J=4.0 Hz); 2.64-2.59 (m, 1H); 2.36 (t,J=12.5 Hz, J=3.0 Hz); 1.19 (d, 3H, J=6.5 Hz)

Examples 2-20 were Prepared According to Method A

Example 2:(R)—N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-3-methyl-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide

¹H-NMR: CDCl3 δ: 8.12 (d, 1H, J=8 Hz), 8.06 (d, 1H, J=8 Hz), 7.92 (s,1H), 7.82 (d, 2H, J=8 Hz), 7.71-7.69 (m, 2H), 7.67 (d, 1H, J=8.5 Hz),7.61 (td, 1H), 7.55-7.49 (m, 2H), 7.37 (t, 1H, J=8 Hz), 7.30 (dd, 1H,J1=1.5 Hz, J2=8 Hz), 7.24 (td, 1H), 6.45 (s, 1H), 4.29 (d, 1H, J=14 Hz),3.84 (td, 1H), 3.72 (t, 1H, J=8.5 Hz), 3.68 (d, 1H, J=14.5 Hz), 3.29(td, 1H), 3.06 (dd, 1H, J=9 Hz, J2=13 Hz), 2.83 (td, 1H, J=8.5 Hz),2.73-2.67 (m, 1H), 2.43 (td, 1H), 1.24 (d, 3H, J=6.5 Hz)

Example 3:(S)—N-(3′-cyano-[1,1′-biphenyl]-3-yl)-2-methyl-4-(3-phenoxybenzyl)piperazine-1-carboxamide

¹H-NMR: CDCl3 δ: 8.04 (d, 1H, J=8 Hz), 7.98 (d, 1H, J=8 Hz), 7.92 (s,1H), 7.81 (d, 2H, J=8 Hz), 7.71-7.69 (m, 2H), 7.65 (d, 1H, J=8.5 Hz),7.61 (td, 1H), 7.55-7.49 (m, 2H), 7.37 (t, 1H, J=8 Hz), 7.30 (dd, 1H,J1=1.5 Hz, J2=8 Hz), 7.24 (td, 1H), 6.45 (s, 1H), 4.29 (d, 1H, J=14 Hz),3.84 (td, 1H), 3.72 (t, 1H, J=8.5 Hz), 3.68 (d, 1H, J=14.5 Hz), 3.29(td, 1H), 3.06 (dd, 1H, J=9 Hz, J2=13 Hz), 2.83 (td, 1H, J=8.5 Hz),2.72-2.67 (m, 1H), 2.43 (td, 1H), 1.22 (d, 3H, J=6.5 Hz)

Example 4:(S)—N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-2-methyl-4-(3-phenoxybenzyl)Piperazine-1-carboxamide

¹H-NMR: CDCl3 δ: 8.15 (d, 1H, J=8 Hz), 8.09 (d, 1H, J=8 Hz), 7.93 (s,1H), 7.82 (d, 2H, J=8 Hz), 7.71-7.67 (m, 4H), 7.66 (d, 1H, J=8.5 Hz),7.61 (td, 1H), 7.55-7.49 (m, 2H), 7.37 (t, 1H, J=8 Hz), 7.30 (dd, 1H,J1=1.5 Hz, J2=8 Hz), 7.24 (td, 1H), 6.45 (s, 1H), 4.29 (d, 1H, J=14 Hz),3.84 (td, 1H), 3.72 (t, 1H, J=8.5 Hz), 3.68 (d, 1H, J=14.5 Hz), 3.29(td, 1H), 3.06 (dd, 1H, J=9 Hz, J2=13 Hz), 2.83 (td, 1H, J=8.5 Hz),2.73-2.67 (m, 1H), 2.43 (td, 1H), 1.21 (d, 3H, J=6.5 Hz)

Example 5:(S)—N-(5-(3-cyanophenyl)pyridin-3-yl)-2-methyl-4-(3-phenoxybenzyl)Piperazine-1-carboxamide

¹H-NMR: CDCl3 δ: 8.11 (d, 1H, J=7.5 Hz), 8.08 (d, 1H, J=8 Hz), 7.94 (s,1H), 7.82 (d, 2H, J=8 Hz), 7.71-7.68 (m, 3H), 7.67 (d, 1H, J=8.5 Hz),7.61 (td, 1H), 7.55-7.49 (m, 2H), 7.37 (t, 1H, J=8 Hz), 7.30 (dd, 1H,J1=1.5 Hz, J2=8 Hz), 7.24 (td, 1H), 6.45 (s, 1H), 4.29 (d, 1H, J=14 Hz),3.84 (td, 1H), 3.72 (t, 1H, J=8.5 Hz), 3.68 (d, 1H, J=14.5 Hz), 3.29(td, 1H), 3.06 (dd, 1H, J=9 Hz, J2=13 Hz), 2.83 (td, 1H, J=8.5 Hz),2.73-2.67 (m, 1H), 2.43 (td, 1H), 1.24 (d, 3H, J=6.5 Hz)

Example 6:N-(3′-Carbamoyl-[1,1′-biphenyl]-3-yl)-4-(quinolin-3-ylmethyl)piperazine-1-carboxamide

¹H NMR (500 MHz, CDCl₃) δ ppm 8.15 (d, 1H, J=8.5 Hz), 8.08 (d, 1H, J=8.5Hz), 8.03 (s, 1H), 7.82 (d, 1H, J=8.5 Hz), 7.75-7.70 (m, 3H), 7.63 (d,2H, J=8.5 Hz), 7.54 (t, 1H, J=7.5 Hz), 7.48 (t, 1H, J=7.5 Hz), 7.40-7.33(m, 2H), 6.70 (s, 1H), 3.88 (s, 2H), 3.57 (t, 4H, J=4.5 Hz), 2.60 (t,4H, J=4.5 Hz)

Example 7:N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-phenylpiperidine-1-carboxamide

¹H NMR (500 MHz, CDCl₃) δ ppm 7.85 (s, 1H); 7.82 (d, 1H, J=7.5 Hz); 7.56(s, 1H); 7.62 (d, 1H, J=7.0 Hz); 7.54 (t, 1H, J=8.0 Hz); 7.39 (t, 1H,J=8.0 Hz); 7.34-7.31 (m, 3H); 7.25-7.21 (m, 5H); 6.53 (S, 1H); 6.24 (d,2H, J=13 Hz); 3.05 (t, 2H, J=12 Hz); 2.74 (tt, 1H, J=3.5 Hz, J=14 Hz)1.96 (d, 2H, J=4.8 Hz); 1.75 (qd, 2H, J=14.0 Hz, J=4.0 Hz)

Example 8:N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-(9H-fluoren-9-yl)piperazine-1-carboxamide

¹H NMR (500 MHz, CDCl₃) δ ppm 8.14 (d, 1H, J=8.5 Hz), 8.09 (d, 1H, J=8Hz), 8.03 (s, 1H), 7.80 (d, 1H, J=8.5 Hz), 7.75-7.70 (m, 3H), 7.64 (d,2H, J=8.5 Hz), 7.56 (t, 1H, J=7.5 Hz), 7.48 (t, 1H, J=7.5 Hz), 7.40-7.33(m, 2H), 6.70 (s, 1H), 3.88 (s, 2H), 3.57 (t, 4H, J=5 Hz), 2.60 (t, 4H,J=5 Hz)

Example 9:N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-(pyridin-2-yl)piperazine-1-carboxamide

¹H NMR (500 MHz, CDCl₃) δ 8.86 (s, 1H); 8.73 (d, 1H, J=2 Hz); 8.54 (d,1H, J=2 Hz); 8.24 (t, 1H, J=2 Hz); 8.16 (s, 1H); 8.02 (d, 1H, J=8.0 Hz);7.89 (d, 1H, J=8.0 Hz); 7.72 (t, 1H, J=8.0 Hz); 7.27-7.32 (m, 4H); 7.20(t, 1H, J=7.5 Hz); 4.31 (d, 2H, J=13 Hz); 2.93 (t, 2H, J=12 Hz); 2.77(tt, J=3.5 Hz, J=12 Hz); 1.83 (d, 2H, J=12 Hz); 1.61 (qd, 2H, J=4 Hz,J=12 Hz)

Example 10:4-([1,1′-biphenyl]-4-ylmethyl)-N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)piperazine-1-carboxamide

¹H NMR (500 MHz, CDCl₃) δ 7.85 (t, 1H, J=2 Hz); 7.81 (dd, 1H, J=12 Hz);7.71 (t, 1H, J=5 Hz); 7.60 (d, 3H, J=12 Hz); 7.57 (s, 1H); 7.48-7.52 (m,2H); 7.45 (t, 1H, J=8 Hz); 7.41 (t, 1H, J=8 Hz); 7.34-7.37 (m, 3H);7.28-7.33 (m, 2H); 7.21 (dt, 1H, J=12 Hz); 6.48 (s, 1H); 3.62 (s, 2H);3.54 (t, 4H, J=5 Hz); 2.54 (t, 4H, J=5 Hz)

Example 11:N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-phenylpiperazine-1-carboxamide

¹H NMR (500 MHz, CDCl₃) δ ppm 7.87 (s, 1H); 7.83 (d, 1H, J=7.5 Hz); 7.57(s, 1H); 7.62 (d, 1H, J=7.0 Hz); 7.53 (t, 1H, J=8.0 Hz); 7.39 (t, 1H,J=8.0 Hz); 7.34-7.31 (m, 3H); 7.25-7.21 (m, 5H); 4.2 (t, 4H, 0.1=5.0Hz); 3.14 (t, 4H, J=5.0 Hz)

Example 12:N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide

¹H NMR (500 MHz, CDCl₃) δ 8.15 (d, 1H, J=8 Hz); 8.08 (d, 1H, J=8.5 Hz);8.01 (s, 1H); 7.81 (d, 1H, J=8.5 Hz); 7.69-7.72 (m, 3H); 7.62 (d, 1H,J=8.5 Hz); 7.56 (t, 1H, J=2 Hz); 7.53 (t, 1H, J=7.0 Hz); 7.46 (t, 1H,J=7.0 Hz); 7.42 (d, 1H, J=8.5 Hz) 7.33 (t, 1H, J=8.0 Hz); 7.24 (t, 1H,J=8.0 Hz); 6.92 (s, 1H); 6.39 (bs, 1H); 5.69 (bs, 1H); 3.85 (s, 2H);3.56 (t, 4H, J=4.5 Hz); 2.56 (t, 4H, J=4.5 Hz)

Example 13:N-(3′-cyano-[1,1′-biphenyl]-3-yl)-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide

¹H NMR (500 MHz, CDCl₃) δ ppm 8.15 (d, 1H, J=8.5 Hz), 8.07 (d, 1H, J=8.5Hz), 8.02 (s, 1H), 7.82 (d, 1H, J=8.5 Hz), 7.75-7.70 (m, 3H), 7.63 (d,2H, J=8.5 Hz), 7.54 (t, 1H, J=7.5 Hz), 7.48 (t, 1H, J=7.5 Hz), 7.40-7.33(m, 2H), 6.70 (s, 1H), 3.86 (s, 2H), 3.57 (t, 4H, J=4.5 Hz), 2.61 (t,4H, J=4.5 Hz).

Example 14:N-(3-phenoxyphenyl)-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide

¹H NMR (500 MHz, CDCl₃) δ 8.15 (d, 1h, J=8 Hz); 8.07 (d, 1H, J=8 Hz);7.81 (d, 1H, J=8 Hz); 7.71 (t, 1H, J=7.5 Hz); 7.62 (d, 1H, J=7.5 Hz);7.53 (t, 1H, J=8.0 Hz); 7.29 (t, 1H, J=8.0 Hz); 7.21 (t, 1H, J=8.0 Hz);6.99-7.11 (m, 5H); 6.67 (d, 1H, J=10 Hz); 6.37 (s, 1H); 3.86 (s, 2H);3.50 (t, 4H, J=5 Hz); 2.58 (t, 4H, J=5 Hz)

Example 15:N-(3′-cyano-[1,1′-biphenyl]-3-yl)-4-phenylpiperidine-1-carboxamide

¹H NMR (500 MHz, CDCl₃) δ ppm 7.87 (s, 1H); 7.83 (d, 1H, J=7.5 Hz); 7.57(s, 1H); 7.62 (d, 1H, J=7.0 Hz); 7.53 (t, 1H, J=8.0 Hz); 7.39 (t, 1H,J=8.0 Hz); 7.34-7.31 (m, 3H); 7.25-7.21 (m, 5H); 6.53 (S, 1H); 6.25 (d,2H, J=13 Hz); 3.04 (t, 2H, J=12 Hz); 2.75 (tt, 1H, J=3.5 Hz, J=14 Hz)1.95 (d, 2H, J=4.8 Hz); 1.76 (qd, 2H, J=14.0 Hz, J=4.0 Hz)

Example 16:N-(5-(3-cyanophenyl)pyridin-3-yl)-4-phenylpiperidine-1-carboxamide

¹H NMR (500 MHz, CDCl₃) δ ppm 8.34 (s, 1H); 7.83 (d, 1H, J=7.5 Hz); 7.57(s, 1H); 7.62 (d, 1H, J=7.0 Hz); 7.51 (t, 1H, J=8.0 Hz); 7.42 (t, 1H,J=8.0 Hz); 7.34-7.31 (m, 3H); 7.25-7.21 (m, 5H); 6.53 (S, 1H); 6.25 (d,2H, J=13 Hz); 3.04 (t, 2H, J=12 Hz); 2.75 (tt, 1H, J=3.5 Hz, J=14 Hz)1.95 (d, 2H, J=4.8 Hz); 1.76 (qd, 2H, J=14.0 Hz, J=4.0 Hz)

Example 17:4-([1,1′-biphenyl]-3-ylmethyl)-N-(3′-cyano-[1,1′-biphenyl]-3-yl)piperazine-1-carboxamide

¹H-NMR: CDCl₃ δ: 8.24 (d, 1H, J=8 Hz), 8.06 (d, 1H, J=8 Hz), 7.92 (s,1H), 7.82 (d, 2H, J=8 Hz), 7.70-7.68 (m, 4H), 7.67 (d, 1H, J=8.5 Hz),7.61 (td, 1H), 7.55-7.49 (m, 2H), 7.37 (t, 1H, J=8 Hz), 7.30 (dd, 1H,J1=1.5 Hz, J2=8 Hz), 7.24 (td, 1H), 6.45 (s, 1H), 4.29 (d, 1H, J=14 Hz),3.82 (td, 1H), 3.72 (t, 1H, J=8.5 Hz), 3.67 (d, 1H, J=14.5 Hz), 3.28(td, 1H), 3.06 (dd, 1H, J=9 Hz, 0.12=13 Hz), 2.83 (td, 1H, J=8.5 Hz),2.71-2.67 (m, 1H), 2.43 (td, 1H), 1.24 (d, 3H, J=6.5 Hz)

Example 18:N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-(3-phenoxybenzyl)piperazine-1-carboxamide

¹H-NMR: CDCl₃ δ: 8.16 (d, 1H, J=8 Hz), 8.10 (d, 1H, J=8 Hz), 7.94 (s,1H), 7.85 (d, 2H, J=8 Hz), 7.71-7.69 (m, 3H), 7.66 (d, 1H, J=8.5 Hz),7.61 (td, 1H), 7.55-7.48 (m, 2H), 7.37 (t, 1H, J=8 Hz), 7.29 (dd, 1H,J1=1.5 Hz, J2=8 Hz), 7.21 (td, 1H), 6.45 (s, 1H), 4.28 (d, 1H, J=14 Hz),3.85 (td, 1H), 3.72 (t, 1H, J=8.5 Hz), 3.69 (d, 1H, J=14.5 Hz), 3.29(td, 1H), 3.06 (dd, 1H, J=9 Hz, J2=13 Hz), 2.83 (td, 1H, J=8.5 Hz),2.72-2.67 (m, 1H), 2.43 (td, 1H), 1.25 (d, 3H, J=6.5 Hz)

Example 19:(S)—N-(3′-cyano-[1,1′-biphenyl]-3-yl)-3-methyl-4-(quinoliylmethyl)piperazine-1-carboxamide

1H-NMR (500 MHz CDCl₃) δ 8.15 (d, 1H, J=8 Hz), 8.06 (d, 1H, J=8 Hz),7.85 (s, 1H), 7.82 (d, 2H, J=8 Hz), 7.72-7.69 (m, 2H), 7.67 (d, 1H,J=8.5 Hz), 7.61 (td, 1H), 7.55-7.49 (m, 2H), 7.37 (t, 1H, J=8 Hz), 7.30(dd, 1H, J=1.5 Hz, J=8 Hz), 7.22 (td, 1H), 6.45 (s, 1H), 4.29 (d, 1H,J=14 Hz), 3.84 (td, 1H), 3.72 (t, 1H, J=8.5 Hz), 3.68 (d, 1H, J=14.5Hz), 3.29 (td, 1H), 3.06 (dd, 1H, J=9 Hz, J=13 Hz), 2.83 (td, 1H, J=8.5Hz), 2.73-2.67 (m, 1H), 2.43 (td, 1H), 1.24 (d, 3H, J=6.5 Hz)

Example 20:N-(3′-Cyano-[1,1′-biphenyl]-3-yl)-4-oxospiro[chromane-2,4′-piperidine]-1′-carboxamide

¹H-NMR: DMSO-d6 δ: 8.71 (s, 1H), 8.04 (s, 1H), 7.95 (d, 1H, J=8 Hz),7.83 (t, 2H, J=2 Hz), 7.74 (dd, 1H, J=1 Hz, J=7.5 Hz), 7.68 (t, 1H, J=8Hz), 7.62-7.55 (m, 2H), 7.63 (t, 1H, J=7.5 Hz), 7.31 (d, 1H, J=8 Hz),7.15-7.05 (m, 3H), 3.92 (td, 2H), 3.270 (t, 2H, J=11 Hz), 2.89 (s, 2H),1.94 (d, 2H, J=13 Hz), 1.76-1.70 (m, 2H)

Method B: Synthesis of Imidazolyl Ureas 10

Imidazolyl ureas 10 (Scheme II) were synthesized by reaction ofsubstituted piperazines 3 (Scheme I) or commercially available arylpiperidines derivatives with 4-nitrophenyl4-phenyl-1H-imidazole-1-carboxylate 9 in THF or DCM without or with abase as triethylamine. Intermediate 9 was synthesized by treatment of4-nitrophenyl chloroformate with commercially available 4-phenylimidazole 8.

The Following Examples were Prepared by Following Method B

Synthesis of Example 21(S)-(4-([1,1′-biphenyl]-3-ylmethyl)-3-methylpiperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanoneStep a) Synthesis of 4-phenylimidazole-4-nitrophenyl Carboxylate 9

To solution of 4-phenyl imidazole (2.2 g, 15.2 mmol) and triethylamine(2.42 mL, 16.7 mmol) in dry THF (20 mL) at 0° C., was added4-nitrophenyl chloroformate (3.1 g, 15.2 mmol) over 15 min period. Thereaction mixture was allowed to warm to room temperature. After 6 hours,the mixture was diluted with EtOAc (100 mL) and washed with saturatedaqueous NaHCO₃ (20 mL). The organic layer was dried over MgSO₄ andconcentrated. The residue was chromatographed to give 2.56 g of4-phenylimidazole-4-nitrophenyl carboxylate 9 as a yellowish whitesolid.

¹H NMR (500 M Hz, CDCl₃) δ 8.30 (d, 2H, J=7.50 Hz); 7.72 (d, 2H, J=7.50Hz); 7.50 (d, 2H, J=7.0 Hz); 7.45-7.41 (m, 4H); 7.28 (s, 1H)

Step b) Synthesis of(S)-(4-([1,1′-biphenyl]-3-ylmethyl)-3-methylpiperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone

To a solution of (S)-1-([1,1′-biphenyl]-3-ylmethyl)-2-methylpiperazine(Scheme I, step b) (0.8 g, 3.17 mmol) in dichloromethane was added4-phenylimidazole-4-nitrophenyl carboxylate (1.13 g, 3.64 mmol) 9 andmixture was stirred at room temperature for 2 hours. Solvent was removedunder reduced pressure. The residue was chromatographed to give(4-([1,1′-biphenyl]-3-ylmethyl)piperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone21 (1.09 g) as a white solid.

1H NMR (500 MHz, CDCl3) 7.98 (s, 1H); 7.81 (d, 2H, J=8.0 Hz); 7.53 (s,1H); 7.41 (t, 2H, J=7.5 Hz); 7.34 (dt, 1H, J=8.0 Hz, J=2.0 Hz);7.11-6.92 (m, 5H, J=8.0 Hz); 6.88-6.81 (m, 4H); 3.97 (dt, 1H, J=13.0 Hz,J=4.5 Hz); 3.85 (dd, 1H, J=13.0 Hz, J=2.0 Hz); 3.72-3.6 (m, 3H); 3.19(qd, 2H, J=13.0, J=3.5 Hz); 2.30 (s, 3H), 1.03 (d, 3H, J=6.0 Hz).

Examples 22-34 were Prepared According to Method B

Example 22:4′(4-Bromo-1H-imidazole-1-carbonyl)spiro[chroman-2,1′-cyclohexan]-4-one

¹H NMR (500 MHz, CDCl₃) 7.89 (d, 1H, J=7.5 Hz); 7.77 (d, 1H, J=2.0 Hz);7.53 (t, 1H, J=8.0 Hz), 7.18 (d, 1H, J=1.0 Hz); 7.06 (t, 1H, J=7.5 Hz,J=1.0 Hz); 7.01 (d, 1H, J=8.0 Hz); 3.96 (d, 2H, J=13.0 Hz), 3.54 (dt,2H, J=13.0 Hz, J=2.0 Hz); 2.77 (s, 2H); 2.20 (d, 2H, J=13.0 Hz), 1.74(dt, 2H, J=13.5 Hz, J=5.0 Hz).

Example 23:(3-Methyl-4-phenylpiperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone

¹H NMR (500 MHz, CDCl₃) 7.96 (s, 1H); 7.81 (d, 2H, J=8.0 Hz); 7.51 (s,1H); 7.41 (t, 2H, J=7.5 Hz); 7.30 (t, 3H, J=7.5 Hz); 6.96 (d as m, 3H,J=8.0 Hz); 4.05 (dt, 1H, J=13.0 Hz, J=4.0 Hz); 3.90-3.82 (m, 1H); 3.77(t, as d, half of A ‘X’ system, 2H, J=4.0 Hz); 3.56 (ddd, 1H, J=26.0J=14.0 Hz J=5.0 Hz); 3.26 (d as m, 1H, J=12.0 Hz, J=3.5 Hz); 2.90 (dt,1H, J=13.0 Hz, J=3.0 Hz); 1.06 (d, 3H, J=7.0 Hz).

Example 24:(3-Methyl-4-phenylpiperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone

¹H NMR (500 MHz, CDCl₃) 7.92 (s, 1H); 7.79 (d, 2H, J=8.0 Hz); 7.51 (s,1H); 7.39 (t, 2H, J=7.5 Hz); 7.28 (dt, 1H, J=8.0 Hz, J=2.0 Hz); 7.10 (d,2H, J=8.0 Hz); 6.89 (d, 2H, J=8.0 Hz); 3.94 (dt, 1H, J=13.0 Hz, J=4.5Hz); 3.80 (dd, 1H, J=13.0 Hz, J=2.0 Hz); 3.72-3.61 (m, 3H); 3.18 (qd,2H, J=13.0, J=3.5 Hz); 1.01 (d, 3H, J=6.0 Hz).

Example 25:(3-Methyl-4-(p-tolyl)piperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone

¹H NMR (500 MHz, CDCl₃) 7.96 (s, 1H); 7.81 (d, 2H, J=8.0 Hz); 7.51 (s,1H); 7.41 (t, 2H, J=7.5 Hz); 7.30 (dt, 1H, J=8.0 Hz, J=2.0 Hz); 7.11 (d,2H, J=8.0 Hz); 6.88 (d, 2H, J=8.0 Hz); 3.96 (dt, 1H, J=13.0 Hz, J=4.5Hz); 3.80 (dd, 1H, J=13.0 Hz, J=2.0 Hz); 3.72-3.6 (m, 3H); 3.18 (qd, 2H,J=13.0, J=3.5 Hz); 2.30 (s, 3H), 1.01 (d, 3H, J=6.0 Hz).

Example 26:(4-(3-(Benzyloxy)phenyl)-3-methylpiperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone

¹H NMR (500 MHz, CDCl₃) 7.91 (s, 1H); 7.81 (d, 2H, J=8.0 Hz); 7.51 (s,1H); 7.41 (t, 2H, J=7.5 Hz); 7.30 (dt, 1H, J=8.0 Hz, J=2.0 Hz);7.11-6.92 (m, 5H, J=: 8.0 Hz); 6.88-6.81 (m, 4H); 3.96 (dt, 1H, J=13.0Hz, J=4.5 Hz); 3.80 (dd, 1H, J=13.0 Hz, J=2.0 Hz); 3.72-3.6 (m, 3H);3.18 (qd, 2H, J=13.0, J=3.5 Hz); 2.30 (s, 3H), 1.01 (d, 3H, J=6.0 Hz).

Example 27:(4-(3-Hydroxyphenyl)-3-methylpiperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone

¹H NMR (500 MHz, CDCl₃) 7.91 (s, 1H); 7.79 (d, 2H, J=8.0 Hz); 7.49 (s,1H); 7.39 (t, 2H, J=7.5 Hz); 7.30 (dt, 1H, J=8.0 Hz, J=2.0 Hz); 7.11 (d,2H, J=8.0 Hz); 6.88 (d, 2H, J=8.0 Hz); 3.96 (dt, 1H, J=13.0 Hz, J=4.5Hz); 3.80 (dd, 1H, J=13.0 Hz, J=2.0 Hz); 3.72-3.6 (m, 3H); 3.18 (qd, 2H,J=13.0, J=3.5 Hz); 2.30 (s, 3H), 1.01 (d, 3H, J=6.0 Hz).

Example 28: (4-(Bis4-fluorophenyl)piperazin-1-yl)(4-bromo-1H-imidazol-1-yl)methanone

¹H NMR (500 MHz, CDCl₃) 7.74 (s, 1H); 7.76 (d, 1H, J=8.0 Hz); 7.34 (dd,4H, J=8.5 Hz, J=5.5 Hz); 7.14 (d, 1H, J=2.0 Hz); 7.01 (t, 4H, J=8.5 Hz);7.34-7.5 (m, 5H); 7.24-7.12 (m, 2H); 4.29 (s, 1H); 3.62 (t, 4H, J=5.0Hz); 2.45 (t, 4H, J=5.0 Hz).

Example 29:(4-(Bis(4-fluorophenyl)methyl)piperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone

¹H NMR (500 MHz, CDCl₃) 7.88 (s, 1H); 7.76 (d, 1H, J=8.0 Hz); 7.43 (s,1H), 7.39 (t, 2H, J=8.0 Hz), (dd, 4H, J=8.0 Hz, J=5.5 Hz); 7.28 (t, 1H,J=7.0 Hz); 7.00 (t, 4H, J=8.0 Hz); 4.30 (s, 1H); 3.67 (t, 4H, J=5.0 Hz);2.47 (t, 4H, J=5.0 Hz).

Example 30:(4-Benzhydrylpiperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone

¹H NMR (400 MHz, CDCl₃) 7.90 (s, 1H); 7.76 (d, 1H, J=8.0 Hz); 7.50-7.40(m, 4H); 7.38 (t, 3H, J=8.5 Hz); 7.34-7.5 (m, 5H); 7.24-7.12 (m, 2H);4.34 (s, 1H); 3.9-3.6 (m, 4H), 2.7-2.4 (m, 4H)

Example 31:(4-Benzhydrylpiperazin-1-yl)(5-benzyl-1H-tetrazol-1-yl)methanone

¹H NMR (400 MHz, CDCl₃) 7.32 (d, 2H, J=8.0 Hz); 7.30-7.27 (m, 8H); 7.25(d, 2H, J=8.0 Hz); 7.21-7.17 (m, 3H); 4.42 (s, 2H); 4.13 (s, 1H), 3.62(t, 2H, J=4.0 Hz); 3.05 (t, 2H, J=4.0 Hz); 2.35 (t, 2H, J=4.0 Hz); 1.95(t, 2H, J=4.0 Hz)

Example 32:(5-Benzyl-1H-tetrazol-1-yl)(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)methanone

¹H NMR (400 MHz, CDCl₃) 7.43 (d, 2H, J=8.0 Hz); 7.40-7.34 (m, 7H);7.10-6.90 (m, 4H); 4.60 (s, 2H); 4.30 (s, 1H), 3.85-3.73 (m, 4H);2.60-2.50 (m, 4H)

Example 33:(3-(Carbomethoxy)-1H-1,2,4-triazol-1-yl)(4-(bis(4-fluorophenyl)methyoxy)Pipe-ridin-1yl)methanone

¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.28 (m, 4H); 7.02 (m, 4H); 5.5(s, 1H); 4.01 (s, 3H), 3.95-3.83 (m, 1H); 3.82-3.68 (m, 4H) 1.95-65 (m,4H)

Example 34:4′-(4-Bromo-1H-imidazole-1-carbonyl)spiro[chromane-2,1′-cyclohexan]-4-one

¹H NMR (500 MHz, CDCl₃) 7.89 (d, 1H, J=7.5 Hz); 7.77 (d, 1H, J=2.0 Hz);7.53 (t, 1H, J=8.0 Hz), 7.18 (d, 1H, J=1.0 Hz); 7.06 (t, 1H, J=7.5 Hz,J=1.0 Hz); 7.01 (d, 1H, J=8.0 Hz); 3.96 (d, 2H, J=13.0 Hz), 3.54 (dt,2H, J=13.0 Hz, J=2.0 Hz); 2.77 (s, 2H); 2.20 (d, 2H, J=13.0 Hz), 1.74(dt, 2H, J=13.5 Hz, J=5.0 Hz).

Method C Syntheses of Substituted Piperazine Carbamates 17

Commercially available substituted aldehydes 11 (Scheme III) weretreated with alkyl, cycloalkyl or aryl Grignard reagents to givesubstituted benzyl alcohols 12, which were converted to correspondingchlorides 13 with thionyl chloride. Chlorides 13 were further treatedwith piperazine to produce alkylated piperazines 14. Commerciallyavailable phenols 15 were converted to chloroformates 16 usingtriphosgene. Final piperazine carbamates 17 were formed by reaction ofchloroformates 16 with alkylated piperazine 14

The Following Examples were Prepared by Following Method C

Example 35 Synthesis of 3-cyanophenyl4-(2-methyl-1-phenylpropyl)piperazine-1-carboxylate Step a) Synthesis of2-methyl-1-phenylpropan-1-ol (12, R₁=H, R_(a)=Isopropyl)

To a solution of commercially available benzaldehyde (1.30 g, 12.30mmol) in THF (25 mL) at −20° C. under a nitrogen atmosphere was addedisopropylmagnesium bromide (4.1 mL, 3.0 M solution in diethyl ether)over 15 min with stirring. Reaction mixture was stirred for additional 1h at −20° C., and upon completion (monitored by TLC) the reactionmixture was diluted with saturated aqueous NH₄Cl solution (10 mL). Theaqueous layer was extracted with EtOAc and the combined organic layerwas dried over MgSO₄ and concentrated in vacuo. The crude material waspurified by column chromatography on silica gel to give benzyl alcohol12 (1.73 g, 11.56 mmol) as colorless liquid.

¹H NMR (400 MHz, CDCl₃) δ 7.35-7.25 (m, 5H); 4.12 (d, 1H, J=6.0 Hz,);2.05-1.90 (m, 1H); 1.92 (brs, 1H) 1.31 (d, 3H, J=6.0 Hz); 1.19 (d, 3H,J=6.0 Hz)

Step b) Synthesis of (1-chloro-2-methylpropyl)benzene (13, R₁=H,R_(a)=Isopropyl)

To a solution of benzyl alcohol 12 (900 mg, 6.0 mmol) in dichloromethane(50 mL) at room temperature was added thionyl chloride (1.1 mL, 15 mmol)drop wise over 10 min. The reaction was refluxed for 1 hour and thenreaction mixture was concentrated in vacuo to give 0.96 g of(1-chloro-2-methylpropyl)benzene 13 as a colorless viscous liquid, whichwas used to the next step without any further purification.

¹H NMR (400 MHz, CDCl₃) δ 7.36-7.27 (m, 5H); 4.67 (d, 1H, J=6.0 Hz);2.05-1.90 (m, 1H); 1.92 (brs, 1H) 1.31 (d, 3H, J=6.0 Hz); 1.19 (d, 3H,J=6.0 Hz)

Step c) Synthesis 1-(2-Methyl-1-phenylpropyl)piperazine (14, R₁=H,R_(a)=Isopropyl)

A solution of name (0.84 g, 5.0 mmol) in ethanol (10 mL) was treatedwith piperazine, (2.15 g, 25.0 mmol) the resulting mixture was heated ina sealed tube at 80° C. for 2 hours with stirring. The reaction mixturewas cooled to room temperature. The solvent was removed in vacuo and theresidue partitioned between dichloromethane and saturated aqueous NaHCO₃solution. The aqueous layer was further extracted with dichloromethane.The combined organic layer was washed with brine, dried over MgSO4 andsolvent removed in vacuum to give 0.98 g of1-(2-methyl-1-phenylpropyl)piperazine as pale yellow viscous liquid.

¹H NMR (400 MHz, CDCl₃) δ 7.36-7.27 (m, 5H); 4.67 (d, 1H, J=6.0 Hz,);3.07 (d, 1H, J=8.0 Hz); 2.50-2.40 (m, 4H); 2.40-2.30 (m, 4H); 2.05-1.90(m, 1H); 2.10 (brs, 1H) 1.31 (d, 3H, J=4.0 Hz); 1.19 (d, 3H, J=8.0 Hz)

Step d) Synthesis of 3-cyanophenyl Chloroformate (16, R₂=CN, R₃=H,W₁=CH)

To a stirred solution of triphosgene (0.5 g, 1.70 mmol) indichloromethane (15 mL) at 0° C. under argon atmosphere was added amixture of commercially available 3-cyanophenol (0.58, 4.87 mmol) andN,N-diisopropylethyl amine (0.87 mL, 5.0 mmol) in methylene chloride (15mL), drop-wise over 10 min. After addition was complete the reactionmixture was stirred at the same temperature for 1 h. When the phenol wasconsumed (TLC analysis) the mixture was diluted with ice-cold water, theaqueous layer was extracted with methylene chloride (2×10 mL), thecombined organic layer was dried over MgSO₄, and the solvent was removedunder reduced pressure to give 0.75 mg of 3-cyanophenyl chloroformate asa pale yellow solid material, which was used in the next step withoutany further purification

Step e) 3-Cyanophenyl4-(2-methyl-1-phenylpropyl)piperazine-1-carboxylate (17, R₁=H,R_(a)=Isopropyl, R₂=CN, R₃=H, W₁=CH)

To a stirred solution of 3-cyanophenyl chloroformate (0.55 g, 3.0 mmol)in methylene chloride (20 mL) at room temperature under argon atmospherewere added 1-(2-methyl-1-phenylpropyl)piperazine (0.79 g, 3.6 mmol) andtriethylamine (0.61 mL, 4.2 mmol) sequentially. The resulting mixturewas stirred at room temperature for 2 hours. after the completion ofreaction, (chloroformate was monitored by TLC), mixture was diluted withwater, the aqueous layer was extracted with methylene chloride (2×10mL), the combined organic layer was dried over MgSO₄ and the solventremoved under reduced pressure to give a crude material, purified bycolumn chromatography on silica gel to give 0.8 g of 3-cyanophenyl4-(2-methyl-1-phenylpropyl)piperazine-1-carboxylate as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, 1H, J=8.0 Hz); 7.42 (t, 2H, J=8.0),7.37 (t, 1H, J=2.0 Hz); 7.34 (t, 2H, J=8.0) overlapping with (m, 1H);7.30-7.27 (m, 1H), 7.13 (d, 2H, J=8.0 Hz); 3.70-3.40 (m, 4H); 3.07 (d,1H, J=8.0 Hz); 2.50-2.40 (m, 2H); 2.40-2.30 (m, 2H); 2.32-2.20 (m, 1H);1.02 (d, 3H, J=4.0); 0.74 (d, 3H, J=8.0)

Examples 36-45 were Prepared According to Method C

Example 36: 3-Cyanophenyl 4-(1-phenylethyl)piperazine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, 4H, J=8.0 Hz); 7.33-7.26 (m, 5H);3.65-3.63 (m, 2H); 3.57-3.55 (m, 2H), 3.46 (s, 1H), 2.53-2.55 (m, 2H);2.48-2.46 (m, 2H); 1.41 (s, 3H)

Example 37: 3-Cyanophenyl4-(cyclopentyl(phenyl)methyl)piperazine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, 1H, J=8.0 Hz); 7.41 (t, 2H, J=8.0Hz), 7.36 (t, 1H, J=2.0 Hz); 7.34 (t, 2H, J=8.0 Hz) overlapping with (m,1H); 7.29-7.26 (m, 1H), 7.13 (d, 2H, J=8.0 Hz); 3.70-3.40 (m, 4H); 3.25(d, 1H, J=7.0 Hz); 2.60-2.45 (m, 3H); 2.40-2.30 (m, 2H); 1.95-1.85 (m,1H); 1.52-1.48 (m, 6H)

Example 38: 3-Cyano-5-hydroxyphenyl 4-benzhydrylpiperazine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, 4H, J=8.0 Hz); 7.30 (t, 4H, J=8.0overlapping with m 1H @ 7.29-7.27); 7.27-7.25 (m, 2H); 7.21 (t, 2H,J=8.0); 4.28 (s, 1H); 3.67-3.60 (m, 2H); 3.59-3.52 (m, 2H); 2.55-2.45(m, 4H)

Example 39: 6-Chloropyridin-2-yl 4-benzhydrylpiperazine-1-carboxylate

¹H NMR (400 M Hz, CDCl₃) δ 7.77 (d, 1H, J=8.0 Hz); 7.58-7.42 (m, 5H);7.40-7.30 (m, 5H); 6.72 (d, 1H, J=8.0 Hz); 6.67 (d, 1H, J=8.0 Hz); 5.28(s, 1H); 4.25-4.15 (m, 4H); 3.50-3.40 (m, 4H)

Example 40: 3-Cyanophenyl4-(bis(4-fluorophenyl)methyl)piperazine-1-carboxylate

¹H NMR (500 M Hz, CDCl₃) δ 7.48 (d as m, 1H, J=8.0 Hz); 7.44 (t, 1H,J=8.0 Hz); 7.42 (d, 1H, J=2.0 Hz); 7.36 (d as m, 3H, J=8.5 Hz); 7.35 (d,2H, J=8.5 Hz); 6.99 (t, 7.36 4H, J=8.5 Hz) 3.69 (brs, 2H); 4.29 (s, 1H);3.66 (brs, 2H); 3.57 (brs, 2H); 2.43 (t, 4H, J=5.0 Hz)

Example 41: 3-Cyanophenyl 4-(9H-fluoren-9-yl)piperazine-1-carboxylate

¹H NMR (500 M Hz DMSO) δ 8.58 (d, 1H J=4.5 Hz); 7.85 (d, 1H, J=8.0 Hz);7.79-7.77 (m as d overlapping with triplets, 2H), 7.65 (d, 1H, J=7.5 Hz,2H); 7.41 (t, 2H, 0.1=7.5 Hz,); 7.34 (t, 2H, J=7.5 Hz,); 5.02 (s, 1H);3.58-3.53 (m, 2H); 3.46-3.41 (m, 2H); 2.65-2.55 (m, 4H).

Example 42: 4-Cyanopyridin-2-yl4-(9H-fluoren-9-yl)piperazine-1-carboxylate

¹H NMR (500 M Hz, CDCl₃) δ 8.58 (d, 1H J=4.5 Hz); 7.85 (d, 1H, J=8.0Hz); 7.79-7.77 (m as d overlapping with triplets, 2H), 7.65 (d, 1H,J=7.5 Hz, 2H); 7.41 (t, 2H, J=7.5 Hz,); 7.34 (t, 2H, J=7.5 Hz,); 5.02(s, 1H); 3.58-3.53 (m, 2H); 3.46-3.41 (m, 2H); 2.65-2.55 (m, 4H)

Example 43: 3-Cyanopyridin-2-yl4-(9H-fluoren-9-yl)piperazine-1-carboxylate

¹H NMR (500 M Hz, CDCl₃) δ 8.58 (d, 1H J=4.5 Hz); 7.82 (d, 1H, J=8.0Hz); 7.79-7.77 (m, 2H), 7.63 (d, 1H, J=7.5 Hz, 2H); 7.41 (t, 2H, J=7.5Hz,); 7.34 (t, 2H, J=7.5 Hz,); 5.02 (s, 1H); 3.58-3.53 (m, 2H);3.46-3.41 (m, 2H); 2.65-2.55 (m, 4H)

Example 44: 3-Cyanophenyl 4-benzhydrylpiperazine-1-carboxylate

¹H NMR (400 M Hz, CDCl₃) δ 7.52-7.49 (m, 2H); 7.4 (t, 1H, J=8.0 Hz);7.39 (td, 1H, J=8.0 Hz, J=2.0 Hz); 7.37-7.34 (m, 5H); 7.31 (m, 1H); 3.69(brs, 2H); 3.58 (s, 2H); 3.55 (brs, 2H); 3.26 (s, 2H); 2.53 (t, 4H,J=5.0 Hz)

Example 45: 5-Cyano-2-fluorophenyl 4-benzylpiperidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.55 (dd, 1H, J=7.0 Hz, J=2.0 Hz); 7.50 (ddd,1H, J=7.0 Hz, J=2.0 Hz, J=2.0 Hz); 7.30 (t, 2H, J=7.0 Hz); 7.25-7.23 (m,1H); 7.22 (t, 1H J=7.0 Hz); 7.16 (t, 1H J=7.0 Hz); 4.25 (d, 1H, J=13.0Hz); 4.19 (d, 1H, J=13.0 Hz); 2.96 (t, 1H, J=13.0 Hz); 2.83 (t, 1H,J=13.0 Hz); 2.59 (d, 2H, J=6.8 Hz); 1.85-1.70 (1H, m overlapping with dat 1.75, 2H, J=13.0 Hz); 1.30 (dq, 2H, J=13.0 Hz, J=4.0 Hz)

Method D: Syntheses of Benzhydryl Piperidine Carbamates 22 andBenzyhydryloxy Piperidine Carbamates 25

Commercially available 1-(tert-butyl) 4-methylpiperidine-1,4-dicarboxylate 18 (Scheme IV), was treated with phenylmagnesium bromide solution in THF to afford benzhydrol 19 which wasconverted by simultaneous dehydration and deprotection to piperidiniumsalt 20. Intermediate 20 was further reduced to piperidine salt 21 viacatalytic hydrogenation. Final carbamates 22 were obtained by treatingpiperidine salt 21 with aryl chloroformates 16 (Scheme III). Benzhydrols23 were converted into corresponding benzhydroxy piperidines 24 viaacid-catalyzed reaction using Dean-Stark condenser. Carbamates 25 wereobtained by reaction of benzhydroxy piperidines 24 with chloroformates16.

The Following Examples were Prepared by Following Method D

Synthesis of Example 46, 3-Cyanophenyl4-benzhydrylpiperidine-1-carboxylate Step a) Synthesis of Tert-butyl4-(hydroxydiphenylmethyl)piperidine-1-carboxylate 19

A stirred solution of commercially available 1-(tert-butyl) 4-methylpiperidine-1,4-dicarboxylate 18 (4.86 g, 20 mmol) in THF (100 mL) at 0°C. was treated with phenyl magnesium bromide (1M solution in THE, 80 mL)over 15 min. and stirred at room temperature for 1 h. Upon completion(monitored by TLC) the reaction mixture was quenched with saturatedaqueous NH₄Cl solution (20 mL). The aqueous layer was extracted withEtOAc and the combined organic layer was washed with brine, dried overMgSO₄ and concentrated in vacuo. The crude material was purified bycolumn chromatography on silica gel to give tert-butyl4-(hydroxydiphenylmethyl)piperidine-1-carboxylate 5.6 g as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ 7.47 (d, 4H, J=8.0 Hz); 7.31 (t, 4H, J=8.0Hz); 7.20 (t, 2H, J=8.0 Hz); 4.25-4.05 (m, 2H); 2.71 (t, 1H, J=12.0 Hz);2.55 (dt, 1H, J=12.0 Hz, J=4.0 Hz); 2.12 (s, 1H); 1.55 (d, 2H, J=12.0Hz); 1.35 (dq 2H, J=12.0 Hz, J=4.0 Hz)

Step b) Synthesis of 4-(diphenylmethylene)piperidinium Trifluoro Acetate20

A solution of tert-butyl4-(hydroxydiphenylmethyl)piperidine-1-carboxylate (5.5 g, 15.0 mmol) andTFA (5.8 mL, 75 mmol) in CH₂Cl₂ (100 mL) at room temperature was stirredovernight and then concentrated. The residue was triturated with 10%EtOAc:Hexane. The precipitating salt was isolated by filtration anddried to give 5.4 g of 4-(diphenylmethylene)piperidinium trifluoroacetate as a white solid.

¹H NMR (400 MHz, DMSO) δ 8.61 (brs, 1H); 8.34 (brs, 1H); 7.40-7.10 (m,10H); 3.40-3.35 (m, 4H); Hz, J=4.0 Hz); 2.55-2.45 (m, 4H)

Step c) Synthesis of 4-(diphenylmethyl)piperidinium Trifluoro Acetate 21

A stirred solution of 4-(diphenylmethylene)piperidinium trifluoroacetate 20 (5.30 g, 14.52 mmol) in methanol was flushed with argon, 10%palladium on carbon (0.8 g, 15% wt/wt) was added and the mixturehydrogenated at atmospheric pressure overnight. The mixture was filteredover celite and celite was further washed with MeOH. The combinedfiltrate was concentrated in vacuo to afford 4.98 g of4-(diphenylmethyl)piperidinium trifluoro acetate as a white solid, whichwas used for the next step without further purification.

¹H NMR (400 MHz, DMSO) δ 8.61 (brs, 1H); 8.34 (brs, 1H); 7.37-7.32 (m,4H); 7.30-7.25 9m, 4H); 7.17-7.10 (m, 2H); 3.59 (d, 1H, J=8.0 Hz);3.25-3.18 (m, 2H); 2.85-2.80 (m, 2H); 2.60-2.48 (m, 1H); 1.54 (d, 2H,J=12.0 Hz); 1.23 (q, 2H, J=12.0 Hz)

Step d) Synthesis of 3-cyanophenyl 4-benzhydrylpiperidine-1-carboxylate

To a stirred solution of 3-cyanophenyl chloroformate 16 (Scheme III,0.64 g, 3.5 mmol,) in methylene chloride (50 mL) at room temperatureunder argon atmosphere were added a piperidine 21 (1.53 g, 4.2 mmol) andtriethylamine (0.5 mL, 3.60 mmol). The resulting mixture was stirred atroom temperature for 2 hours. After the completion of reaction, asmonitored by TLC, the mixture was diluted with water, the aqueous layerwas extracted with methylene chloride (2×20 mL), the combined organiclayer was dried with MgSO₄, The solvent was removed under reducedpressure to give a crude material, which was purified by columnchromatography on silica gel to afford 0.9 g of 3-cyanophenyl4-benzhydrylpiperidine-1-carboxylate as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.47-7.41 (m, 3H); 7.36 (dt, 1H, J=8.0,J=2.0); 7.32-7.25 (m, 9H); 7.22-7.15 (m, 2H); 4.20 (d, 2H, J=13.0 Hz);3.54 (d, 1H J=6.8 Hz); 2.96 (dt, 2H, J=13.0, J=2.0); 2.42-2.30 (m, 1H);1.67 (d, 2H, J=13.0); 1.20 (dq, 2H, J=13.0, J=2.0)

Step e) Synthesis of4-(4-chlorophenyl)(2-chloropyridin-3-yl)methoxypiperidine (24, W₁=N,R₄=2-Cl, R₅=4-Cl)

A mixture of 4-(4-chlorophenyl)(2-chloropyridin-3-yl)methamol (2.54 g,10.0 mmol; prepared according to Hart et al Biorg. & Med. Chem. Lett.2009, 19: 4241-4244), 4-hydroxypiperidine (1.0 g, 10.0 mmol), andp-toluenesulfonic acid monohydrate (4.19 g 22.0 mmol) in toluene (50 mL)was refluxed with a Dean-Stark condenser for 3 h. After cooling to roomtemperature, the toluene solution was washed with saturated aqueousNaHCO₃, and dried over MgSO₄. The solvent was removed under reducedpressure to give 2.52 g of4-(4-chlorophenyl)(2-chloropyridin-3-yl)methoxypiperidine as a paleyellow gum.

¹H NMR (400 MHz, CDCl₃) δ 8.37 (dd, 1H, J=8.0 Hz, J=2.0 Hz); 7.82 (dd,1H, J=8.0 Hz); 7.5-7.42 (m, 3H); 7.38-7.28 (m, 6); 5.90 (s, 1H);3.72-3.65 (m, 1H); 3.32-3.55 (m, 4H); 2.10 9brs, 1H); 1.90-1.80 (m, 2H);1.79-1.70 (m, 2H)

Step f) 3-Cyanophenyl4-((4-chlorophenyl)(2-chloropyridin-3-yl)methoxy)piperidine-1-carboxylate

3-Cyanophenyl4-((4-chlorophenyl)(2-chloropyridin-3-yl)methoxy)piperidine-1-carboxylatewas prepared from a solution of 3-cyanophenyl chloroformate (Scheme III,0.45 g, 2.5 mmol) methylene chloride (40 mL),4-(4-chlorophenyl)(2-chloropyridin-3-yl)methoxypiperidine 24 (1.0 g, 3.0mmol) and triethyl amine (0.86 mL, 6.20 mmol) to afford 0.84 g of3-cyanophenyl4-((4-chlorophenyl)(2-chloropyridin-3-yl)methoxy)piperidine-1-carboxylateas a white solid.

¹H NMR (400 MHz, CDCl₃) δ 8.34 (dd, 1H, J=8.0 Hz, J=2.0 Hz); 7.92 (d,1H, J=8.0); 7.52-7.41 (m, 3H) 7.41-7.28 (m, 6H); 5.89 (s, 1H), 3.95-3.75(m, 2H); 3.80-3.65 (m, 1H); 3.50-3.30 (m, 2H); 3.49-3.39 (m, 1H);1.95-1.85 (m, 2H); 1.80-1.70 (m, 2H).

Examples 47-51, 54-58 were Synthesized by Method D.

Example 47: 3-Cyanophenyl 4-(diphenylmethylene)piperidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.54-7.44 (m, 2H) overlapping with (d, @7.481H, J=8.0 Hz); 7.40 (d, 1H, J=8.0 Hz), 7.33 (t, 4H, J=7.2 Hz); 7.24 (t,2H, J=7.2 Hz) 7.14 (d, 4H, J=8.0 Hz); 3.75-3.64 (m, 2H); 3.62-3.52 (m,2H); 2.52-2.40 (m, 4H)

Example 48: 3-(Methoxycarbonyl)phenyl4-(diphenylmethylene)piperidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.54 (t, 1H J=2.0); 7.4-7.32 (m, 1H);7.30-7.15 (m, 8H); 7.10-7.02 (m, 4H); 3.81 (s, 3H); 3.70-3.56 (m, 4H);2.50-2.40 (m, 4H)

Example 49: 5-Cyano-2-fluorophenyl 4-benzhydrylpiperidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.53 (dd, 1H, J=7.0 Hz, J=2.0 Hz); 7.49 (ddd,1H, J=7.0 Hz, J=2.0, J=2.0); 7.35-7.25 (m, 8H); 7.25-7.22 (m, 1H);7.22-7.15 (m, 2H); 4.22 (d, 1H, J=13.0 Hz); 4.17 (d, 1H, J=13.0 Hz);3.54 (d, 1H, J=7.0); 3.0 (t, 1H, J=13.0 Hz); 2.86 (t, 1H, J=13.0 Hz);2.40-2.30 (m, 1H); 1.67 (d, 2H, 0.1=13.0); 1.25 (dq, 2H, 0.1=13.0,J=2.0)

Example 50: 3-Cyano-5-hydroxyphenyl 4-benzhydrylpiperidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.35-7.27 (m, 8H); 7.22-7.15 (m, 2H); 6.89 (s,1H); 6.89 (s, 1H); 6.79 (s, 1H); 4.19 (d, 2H J=13.0); 3.56 (d, 1HJ=7.0); 3.05-2.75 (m, 2H); 2.37-2.31 (m, 2H); 1.67 (d, 2H, J=13.0); 1.30(dq, 2H, J=13.0, J=2.0)

Example 51: 6-Chloropyridin-2-yl4-(hydroxydiphenylmethyl)piperidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.70 (t, 1H, J=8.0 Hz); 7.47 (d, 4H, J=8.0Hz); 7.32 (d, 4H, J=8.0 Hz); 7.24-7.22 (m, 1H, (, 4H, overlapping with tat δ 7.21 2H, J=8.0 Hz); 4.30 (t, 2H, J=13.0 Hz); 3.05 (t, 1H, J=13.0Hz); 2.88 (t, 1H, J=13.0 Hz); 1H); 1.67 (d, 1H, J=13.0 Hz); 1.45 (dq,2H, J=13.0 Hz, J=2.0 Hz)

Example 52: 3-Cyanophenyl 4-benzylpiperidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.49-7.42 (m, 3H); 7.37 (td, 1H, J=7.0 Hz,J=2.0 Hz); 7.31 (t, 2H, J=7.0 Hz); 7.22 (d, 1H, J=8.0 Hz); 7.16 (d, 1H,J=8.0 Hz); 4.23 (t, 2H, J=12.0 Hz); 2.94 (t, 1H, J=12.0 Hz); 2.81 (t,1H, J=12.0 Hz); 2.60 (d, 2H, J=6.8 Hz); 1.74 (d, 2H, J=12.0 Hz); 1.27(dq, 2H, J=12.0 Hz, J=4.0 Hz)

Example 54 6-Chloropyridin-2-yl 4-(benzhydryl)piperidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.70 (t, 1H, J=8.0 Hz); 7.35-7.25 (m, 9H);7.25-7.15 (m, 3H); 7.05 (d, 1H, J=8.0 Hz); 4.20 (t, 2H, 0.1=13.0 Hz);3.55 (d, 1H, J=6.0 Hz); 3.0 (t, 1H, J=13.0 Hz); 2.85 (t, 1H, J=13.0 Hz);2.4-2.2 (m, 1H), 1.7-1.55 (m, 2H); 1.25 (dq, 2H, J=13.0 Hz, J=2.0 Hz)

Example 55: 3-(Methoxycarbonyl)phenyl4-(benzhydryloxy)piperidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) 7.62 (d, 2H, J=8.0 Hz); 7.55-7.42 (m, 2H);7.40-7.28 (m, 8H); 7.02 (d, 2H, J=8.0 Hz); 5.55 (s, 1H); 3.94 (s, 3H);3.90-3.76 (m, 3H); 3.7-3.35 (m, 2H); 1.92-1.85 (m, 4H)

Example 56: 5-Cyano-2-fluorophenyl4-(benzhydryloxy)piperidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.55 (dd, 1H, J=7.0 Hz, J=2.0 Hz); 7.51-7.49(m, 1H); 7.38-7.30 (m, 8H) 7.27 (t, 2H, J=7.0 Hz); 7.18-7.15 (m, 1H);5.54 (s, 1H), 3.95-3.85 (m, 1H); 3.82-3.75 (m, 1H); 3.74-3.68 (m, 1H);3.60-3.50 (m, 1H); 3.49-3.39 (m, 1H); 1.92-1.84 (m, 2H); 1.83-1.80 (m,2H)

Example 57: 6-Chloropyridin-2-yl4-(benzhydryloxy)piperidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.71 (t, 1H, J=8.0 Hz); 7.36-7.31 (m, 7H);7.28-7.24 (m, 3H); 7.21 (d, 1H, J=8.0 Hz); 7.07 (d, 1H, J=8.0 Hz); 5.53(s, 1H); 3.95-3.87 (m, 1H); 3.86-3.76 (m, 1H); 3.75-3.65 (m, 1H);3.58-3.48 (m, 1H); 3.47-3.37 (m, 1H); 1.90-1.82 (m, 2H); 1.81-1.72 (m,2H)

Example 58: 3-Cyanophenyl 4-(benzhydryloxy)piperidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.49-7.46 (m, 1H); 7.45-7.41 (m, 2H);7.39-7.33 (m, 8H); 7.32-7.27 (m, 3H); 5.60 (s, 1H); 3.95-3.75 (m, 2H);3.74-3.68 (m, 1H); 3.55-3.40 (m, 2H); 1.93-1.87 (m, 2H); 1.84-1.74 (m,2H)

Method E: Synthesis of 4-arylsulfonylpiperidine Carbamates 29 and4-arylsulfonylpiperazine Carbamates 32

Synthesis started from tert-butyl(4-4-Bromophenyl)thiopiperidine-1-carboxylate (26), which was preparedas per literature procedure (Fletcher et al. J. Med. Chem. (2002) 45:492-503). Piperidinethioether 26 was oxidized to sulfone 27 with m-CPBAand the N-BOC group was deprotected with TFA, to give piperidinium TFAsalt 28, which was treated with aryl chloroformates 16, to give sulfonylpiperidine carbamates 29. Commercially available aryl sulfonyl chlorides30 were treated with piperazine to give corresponding1-(arylsulfonyl)piperazine derivatives 33, which were converted in tocarbamate derivatives 32, by treating with aryl chloroformates 16, asshown in scheme V.

The Following Examples were Prepared by Following Method E

Synthesis of Example 59, 3-Cyanophenyl4-(4-bromophenylsulfonyl)piperidine-1-carboxylate Step a) Synthesis ofTert-butyl 4-((4-bromophenyl)sulfonyl)piperidine-1-carboxylate (27)

To a solution of name (2.1 g, 5.6 mmol) in dichloromethane (50 mL) at 0°C. was added of m-CPBA (2.1 g, 12.4 mmol) and the solution was stirredat room temperature overnight hours. The solution was diluted with waterand washed with 10 percent aqueous Na₂SO₃ solution and saturated aqueousNaHCO₃ solution, sequentially. The organic layer was dried overmagnesium sulfate and the solvent removed under reduced pressure toafford 2.1 g of tert-butyl4-((4-bromophenyl)sulfonyl)piperidine-1-carboxylate as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.71 (s, 4H); 4.35-4.25 (m, 2H): 3.10-2.90 (m,1H); 2.70-2.55 (m, 2H); 1.96 (d, 2H, J=8.0 Hz); 1.58 (d, 2H, J=12.0 Hz);1.43 (s, 9H)

Step b) Synthesis of 4-((4-bromophenyl)sulfonyl)piperidinium TrifluoroAcetate (28)

A solution of tert-butyl4-((4-bromophenyl)sulfonyl)piperidine-1-carboxylate (2.0 g, 4.96 mmol)and TFA (1.9 mL, 24.8 mmol) in CH₂Cl₂ (20 mL) at rt. was stirredovernight and then concentrated. The residue was triturated with 10%EtOAc:Hexane. The precipitating salt was isolated by filtration anddried to give 1.9 g of 4-((4-bromophenyl)sulfonyl)piperidinium trifluoroacetate as a white solid.

¹H NMR (400 MHz, DMSO) δ 8.60 (brs, 1H); 8.33 (brs, 1H); 7.82 (d, 2H,J=8 Hz); 7.78 (d, 2H, J=8 Hz); 3.46 (d, 2H, J=8.0 Hz); 2.97 (t, 1H,J=12.0 Hz); 2.16 9 (d, 2H, J=12.0 Hz); 1.90 (d, 2H, J=8.0 Hz)

Step c) 3-Cyanophenyl 4-(4-bromophenylsulfonyl)piperidine-1-carboxylate

To a stirred solution of the of 3-cyanophenyl chloroformate (Scheme III,0.10 g, 0.55 mmol) in methylene chloride at room temperature under argonatmosphere were added 4-((4-bromophenyl)sulfonyl)piperidinium trifluoroacetate (0.27 g, 0.66 mmol) and triethyl amine (0.18 g, 1.32 mmol),sequentially. The resulting mixture was stirred at room temperature for2 h. After the completion of reaction, as monitored by TLC, mixture wasdiluted with water, the aqueous layer was extracted with methylenechloride, the combined organic layer was dried over MgSO₄, and thesolvent removed under reduced pressure to give a crude material,purified by column chromatography on silica gel to give 3-cyanophenyl4-(4-bromophenylsulfonyl)piperidine-1-carboxylate as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.72 (s, 4H); 7.55-7.45 (m, 2H); 7.43-7.40 (m,1H); 7.35 (d, 1H, J=8.0 Hz); 4.5-4.30 (m, 4H); 3.20-3.12 (m, 1H);3.10-3.0 (m, 1H); 2.92-2.80 (m, 2H); 2.20-2.05 (m, 2H); 1.90-1.70 (m,2H)

Step d) Synthesis of 4-tolylsulfonylpiperazine (31, R₂=Me)

To a stirred solution of p-tolylsulfonyl chloride 31 (1.90 g, 10.0 mmol)in methylene chloride (50 mL) at 0° C. was added piperazine (0.95 g,11.0 mmol) and triethyl amine (1.1 g, 11.0 mmol). The mixture wasstirred at 0° C. for 10 min and at room temperature under argonatmosphere for 2 h. After the completion of reaction, as monitored byTLC, mixture was diluted with water. The aqueous layer was extractedwith methylene chloride, and the combined organic layer was dried overMgSO₄. The solvent removed under reduced pressure to give 2.1 g of4-tolylsulfonylpiperazine as a white solid, used in next step withoutfurther purification.

¹H NMR (400 MHz, CDCl₃) δ 7.65 (d, 2H, J=8.0 Hz); 7.43 (d, 2H, J=8.0Hz); 3.07 (m, 4H); 2.60-2.51 (m, 4H); 2.45 (s, 3H)

Examples 60-66 were Synthesized by Method E.

Example 60: 5-Cyano-2-fluorophenyl4-(4-bromophenylsulfonyl)piperidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.76 (s, 4H); 7.60-7.50 (m, 1H); 7.30-7.20 (m,2H); 4.5-4.30 (m, 4H); 3.20-3.12 (m, 1H); 3.10-3.0 (m, 1H); 2.92-2.80(m, 2H); 2.20-2.05 (m, 2H); 1.90-1.70 (m, 2H)

Example 61: 5-Cyano-2-methylphenyl4-(4-bromophenylsulfonyl)piperidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.76 (s, 4H); 7.41 (dd, 1H, J=8.0 Hz, J=2.0Hz); 7.35 (d, 1H, J=2.0 Hz); 7.30 (d, 1H, J=8.0 Hz); 4.43 (d, 1H, J=12.0Hz); 4.37 (d, 1H, J=12.0 Hz); 3.13 (tt, 1H, J=12.0 Hz, J=4.0 Hz); 3.08(t, 1H, J=12.0 Hz); 2.87 (t, 1H, J=12.0 Hz); 2.23 (s, 3H); 2.20-2.0 (m,2H); 1.85-1.68 (m, 2H)

Example 62: 5-Cyano-2-methoxyyphenyl4-(4-bromophenylsulfonyl)piperidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.76 (s, 4H); 7.51 (dd, 1H, J=8.0 Hz, J=2.0Hz); 7.35 (d, 1H, J=2.0 Hz); 6.98 (d, 1H, J=8.0 Hz); 4.42 (d, 1H, J=12.0Hz); 4.33 (d, 1H, J=12.0 Hz); 3.88 (s, 3H); 3.11 (tt, 1H, J=12.0 Hz,J=4.0 Hz); 2.99 (t, 1H, J=12.0 Hz); 2.82 (t, 1H, J=12.0 Hz); 2.12-1.95(m, 2H); 1.90-1.70 (m, 2H)

Example 63: 2,6-Difluorophenyl4-(4-bromophenylsulfonyl)piperidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.76 (s, 4H); 7.42 (m, 2H); 7.27 (t, 1H, J=8.0Hz); 4.43 (d, 1H, J=12.0 Hz); 4.32 (d, 1H, J=12.0 Hz); 3.89 (s, 3H);3.10 (tt, 1H, J=12.0 Hz, J=4.0 Hz); 2.99 (t, 1H, J=12.0 Hz); 2.81 (t,1H, J=12.0 Hz); 2.10-1.92 (m, 2H); 1.91-1.72 (m, 2H)

Example 64: 4-Bromophenyl 4-tosylpiperazine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.65 (d, 2H, J=8.0 Hz); 7.43 (d, 2H, J=8.0Hz); 7.36 (d, 2H, J=8.0 Hz); 6.92 (d, 2H J=8.0); 3.78-3.72 (m, 2H);3.72-3.62 (m, 2H); 3.07 (t, 4H, J=4.0 Hz); 2.45 (s, 3H)

Example 65: 2,6-Difluorophenyl 4-tosylpiperazine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.6 (d, 2H, J=8.0 Hz); 7.33 (d, 2H, J=8.0 Hz);7.19-7.09 (m, 1H); 6.93 (t, 2H, J=8.0 Hz); 3.90-3.80 (m, 2H); 3.7-0-3.60(m, 2H); 3.05-3.15 (t, 4H, J=4.0 Hz); 2.46 (s, 3H)

Example 66: 4′-Fluoro-3-hydroxy-[1,1′-biphenyl]-4-yl4-tosylpiperazine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ 7.67 (d, 2H, J=8.0 Hz); 7.60 (d, 1H, J=8.0Hz); 7.50-7.40 (m, 2H); 7.39-7.22 (m, 3H); 7.15 (t, 1H, J=2.0 Hz); 7.08(dt, 2H, J=8.0 Hz, J=2.0 Hz); 6.70 (brs, 1H); 3.88-3.78 (m, 2H);3.75-0-3.68 (m, 2H); 3.15-3.05 (m, 4H); 2.47 (s, 3H)

Method F: Synthesis ofN-(3-(1,1-dioxidothiomorpholino)phenyl)-4-phenylpiperazine/piperidineUreas 38

Commercially available 3-nitro bromobenzene 33 (Scheme VI) was coupledwith thiomorpholine under Buchwald condition reference to give4-(3-nitrophenyl)thiomorpholine 34. Sulfide was oxidized to sulfones 35,followed by catalytic reduction of the nitro group to give amine 36,which was converted into its phenyl carbamate 37, by reacting withphenyl chloroformate. Finally, N-aryl ureas 38 were obtained by reactingcommon intermediate phenyl carbamate 37 with aryl piperazine3/commercially available phenyl piperidine under microwave irradiationcondition

The Following Examples were Prepared by Following Method F

Synthesis of Example 67,N-(3-(1,1-Dioxidothiomorpholino)phenyl)-4-phenylpiperazine-1-carboxamideStep a) Synthesis of 4-(3-nitro-phenyl)-thiomorpholine 34

Pd₂(dba)₃ (0.362 g, 0.3 mmol), xantphos (0.343 g, 0.5 mmol), K₂CO₃ (1.91g, 13.8 mol) were added to a flask containing dioxane the mixture wasflushed with nitrogen gas for 10 min, followed by the addition of1-bromo-3-nitro-benzene (2.0 g, 9.8 mmol) and thiomorpholine (1.2 g, 1.8mmol) and the flask was refluxed overnight. The reaction was monitoredby the TLC (20% EtOAc: hexane). The reaction mixture was then filteredthrough celite, and the filterate was concentrated. The crude productwas purified by column chromatography (10% ethyl acetate in hexane) toafford 1.8 g of 4-(3-nitro-phenyl)-thiomorpholine as colorless liquid.

¹H NMR (500 M Hz, CDCl₃) δ 7.87 (s, 1H); 7.82 (d, 1H, J=8 Hz); 7.48 (t,1H, J=8.5 Hz); 7.37-7.34 (m, 1H); 3.81 (t, 2H, J=5.5 Hz); 3.65 (t, 2H,J=6.0 Hz); 3.57 (t, 2H, J=5.5 Hz); 3.50 (t, 2H, J=5.5 Hz)

Step b) Synthesis of 4-(3-nitro-phenyl)-thiomorpholine 1,1-dioxide 35

To a stirred solution of 4-(3-nitro-phenyl)thiomorpholine 34 (1.8 g, 8.0mmol) in DCM (25 mL) maintained at 10-15° C. was added mCPBA (3.2 g,20.0 mmol) The mixture was stirred at 10-15° C. for 30 min and at roomtemperature overnight. After completion of reaction (monitored by theTLC, 5% methanol: chloroform), the reaction mixture was washed withsaturated NaHCO₃. The aqueous layer was extracted with ethyl acetate,the combined organic layer was washed with brine solution, dried overNa₂SO₄, and concentrated to get the crude product which was purified bycolumn chromatography to afford 1.5 g of4-(3-Nitro-phenyl)-thiomorpholine 1,1-dioxide as pale yellow solid.

¹H NMR (500 M Hz, CDCl₃) δ 7.93 (s, 1H); 7.91 (d, 1H, J=8 Hz); 7.50 (t,1H, J=8.5 Hz); 7.37-7.35 (m, 1H); 4.29 (t, 2H, J=5.5 Hz); 3.75 (t, 2H,J=6.0 Hz); 3.57 (t, 2H, J=5.5 Hz); 3.50 (t, 2H, J=5.5 Hz)

Step c) Synthesis of 3-(1,1-dioxothiomorpholin-4-yl)-phenylamine 36

To a solution of 4-(3-nitro-phenyl)-thiomorpholine 1, 1-dioxide (1.5 g,0.0058 mol) in MeOH (20 mL) in an atmosphere of argon gas was added 10%Pd—C (200 mg) and the reaction was carried out under H₂ gas pressurenumber?. The reaction was monitored by the TLC. The reaction mixture wasfiltered through celite and concentered to afford 1.0 g of3-(1,1-dioxothiomorpholin-4-yl)-phenylamine as a white solid.

¹H NMR (500 M Hz, Acetone d₆) δ 6.81 (t, 1H, J=8 Hz); 6.01-5.95 (m, 3H);4.80 (t, 1H, J=5 Hz); 4.38 (bs, 2H); 4.00 (t, 2H, J=5 Hz); 3.59 (q, 2H,J=7.0 Hz); 3.37 (t, 2H, J=7.0 Hz); 3.27 (t, 2H, J=7.0 Hz)

Step d) Synthesis of Phenyl(3-(1,1-dioxidothiomorpholino)phenyl)carbamate 37

To solution of 3-(1,1-dioxo-116-thiomorpholin-4-yl)-phenylamine in dryTHF (30 mL) at 0° C., was added phenyl chloroformate (1.0 g, 0.8 mL)drop wise over 15 min period. The reaction mixture was allowed to warmto room temperature. After 12 h, the mixture was diluted with EtOAc (100mL) and washed with saturated aqueous NaHCO₃ (20 mL). The organic layerwas dried over MgSO₄ and concentrated. The residue was chromatographedto give 1.24 g of phenyl (3′-carbamoyl-[1,1′-biphenyl]-3-yl)carbamatesas a white solid.

¹H NMR (500 M Hz, CDCl₃) δ 7.49 (t, 1H, J=8.0 Hz); 7.31-7.28 (m, 3H);7.11 (t, 2H, J=7.5 Hz); 6.90-6.81 (m, 3H); 3.89 (t, 2H, J=5.0 Hz); 3.10(t, 2H, J=5.0 Hz)

Step e) Synthesis ofN-(3-(1,1-dioxidothiomorpholino)phenyl)-4-phenylpiperazine-1-carboxamide(38, Ar₁=Ph, X=N, R₁=H)

A solution of phenyl piperazine (0.6 g, 3.69 mmol) and phenyl(3-(1,1-dioxidothiomorpholino)phenyl) carbamate (1.28 g, 3.69 mmol) inacetonitrile was heated in a sealed tube under microwave irradiation at120° C. for 10 min with stirring. The reaction mixture was cooled toroom temperature and solvent was removed under reduced pressure. Thecrude material was partitioned between dichloromethane and water. Theaqueous phase was extracted with dichloromethane. The combined extractswere dried over MgSO₄ and concentrated. Chromatography of the residuegave 1.28 g ofN-(3-(1,1-dioxidothiomorpholino)phenyl)-4-phenylpiperazine-1-carboxamideas white solid.

¹H NMR (500 M Hz, CDCl₃) δ 7.31 (t, 2H, J=8 Hz); 7.25-7.19 (m, 3H); 7.06(t, 1H, J=8 Hz); 6.98 (bs, 1H); 6.68 (bs, 1H), 6.48 (d, 1H, J=7.5 Hz);4.24 (t, 4H, J=5.0 Hz); 3.65 (t, 4H, J=5 Hz); 3.37 (t, 2H, J=5 Hz); 3.17(t, 2H, J=5 Hz); 2.96 (t, 2H, J=8 Hz); 2.70 (t, 2H, J=8 Hz)

Example 68 was Prepared by Method F Example 68N-(3-(1,1-dioxidothiomorpholino)phenyl)-4-phenylpiperidine-1-carboxamide

¹H NMR (500 M Hz, CDCl₃) δ 7.31 (t, 2H, J=8 Hz); 7.25-7.19 (m, 3H); 7.06(t, 1H, J=8 Hz); 6.98 (bs, 1H); 6.68 (bs, 1H), 6.48 (d, 1H, J=7.5 Hz);4.20 (d, 3H, J=13.5 Hz); 4.0 (t, 3H, J=5 Hz); 3.65 (t, 2H, J=5 Hz); 3.37(t, 2H, J=5 Hz); 3.17 (t, 2H, J=5 Hz); 2.96 (t, 2H, J=8 Hz); 2.70 (tt,1H, J=12 Hz); 1.91 (d, 2H, J=12 Hz); 1.74-1.65 (qd, 2H, J=12.5 Hz, J=4.0Hz)

Method G: Synthesis of 1,1-dioxidothiomorpholin-1-ylphenyl Carbamates 42

3-Amino phenol (Scheme VII) was reacted with divinyl sulfone underbis-aza micheal condition (Halimehjnai et al (Synthetic Communications,(2013) 43 191-197) to afford 4-(3-hydroxyphenyl) thiomorpholine1,1-dioxide 40, which was converted into its chloroformate 41 withphosgene solution in toluene. Chloroformate 41 was converted to arylcarbamates by reaction with aryl piperazine 3 (Scheme I) or commerciallyavailable aryl piperidine derivatives.

The Following Examples were Prepared by Following Method G

Synthesis of Example 69: 3-(1,1-Dioxidothiomorpholino)phenyl4-phenylpiperazine-1-carboxylate Step a) Synthesis of4-(3-hydroxyphenyl)thiomorpholine 1,1-dioxide 40

Water (30 mL), boric acid (30 mol %), and glycerol (6 drops) were addedto a stirred solution of 3-amino phenol 39 (3.2 g, 29.32 mmol) anddivinyl sulfone (3.46 g, 29.32 mmol). The resulting mixture was stirredunder reflux for 3 h. The reaction mixture was extracted with ethylacetate, and the organic layer was washed three times with water. Afterthe solvent was evaporated, the crude product was washed with hotpetroleum ether, to give 4-(3-hydroxyphenyl)thiomorpholine 1,1-dioxide6.21 g, as white solid.

¹H NMR (500 M Hz, CDCl₃) δ 7.26 (t, 1H, J=8.0 Hz); 6.48 (dd, 1H, J=8.0Hz, J=2.5 Hz); 6.40-6.37 (m, 3H); 5.15 (bs, 1H,); 3.85 (t, 2H, J=5.0Hz); 3.08 (t, 2H, J=5.0 Hz)

Step b) Synthesis of 3-(1,1-dioxidothiomorpholino)phenyl Chloroformate41

To a stirred solution of triphosgene (0.52 g, 1.54 mmol) indichloromethane at 0° C. under argon atmosphere was added a mixture ofthe 4-(3-hydroxyphenyl)thiomorpholine 1,1-dioxide (1.0 g, 4.39 mmol) andN,N-diisopropylethyl amine (1.3 mL) in methylene chloride drop wise.After addition was complete the reaction mixture was gradually warmed toroom temperature and stirred for 1 h. After the completion of thereaction, as monitored by TLC, the mixture was diluted with ice-coldwater, the aqueous layer was extracted with methylene chloride. Thecombined organic layer was dried over MgSO₄, and the solvent was removedunder reduced pressure to give 3-(1,1-dioxidothiomorpholino)phenylchloroformate 1.12 g, white solid, which was used in the next stepwithout any further purification, as.

¹H NMR (500 M Hz, CDCl₃) δ 7.33 (t, 1H, J=8.0 Hz); 6.85-6.81 (m, 3H);3.87 (t, 4H, J=5.0 Hz); 3.10 (t, 4H, J=5.0 Hz)

Step c) Synthesis of 3-(1,1-dioxidothiomorpholino)phenyl4-phenylpiperazine-1-carboxylate (42, Ar₁=Ph, X=N)

To a stirred solution of the 3-(1,1-dioxidothiomorpholino)phenylchloroformate (1.3 g, 4.49 mmol) in methylene chloride (10 mL) at roomtemperature under argon atmosphere was added 4-phenylpiperazine (0.74 g,4.48 mmol) and triethylamine (1.1 mL, 4.92 mmol) in methylene chloride.The resulting mixture was stirred at room temperature for 2 h. After thecompletion of reaction, as monitored by TLC, mixture was diluted withwater, the aqueous layer was extracted with methylene chloride, thecombined organic layer was dried over MgSO₄. The solvent was removedunder reduced pressure to give crude material, which were purified bycolumn chromatography on silica gel to give 1.08 g of3-(1,1-dioxidothiomorpholino)phenyl 4-phenylpiperazine-1-carboxylate aswhite solid.

¹H NMR (500 M Hz, CDCl₃) δ 7.33 (t, 2H, J=5.0 Hz); 7.29 (d, 1H, J=7.5.0Hz); 6.97 (d, 2H, J=7.5 Hz); 6.93 (t, 1H, J=7.5 Hz); 6.75 (dd, 1H, J=7.5Hz, J=2.0 Hz); 6.72-6.68 (m, 2H), 3.86 (m as t, 4H, J=5.5 Hz); 3.84-3.78(m, 2H); 3.76-3.70 (m, 2H) 3.24 (m as t, 4H, J=5.5 Hz), 3.01 (m as t,4H, J=5.0 Hz)

Examples 70-73 were Prepared by Method F

Example 70: 3-(1,1-Dioxothiomorpholin-4-yl)phenyl4-phenylpiperidine-1-carboxylate

¹H NMR (500 MHz, CDCl₃) δ 7.34 (t, 2H, J=8.0 Hz); 7.28 (t, 2H, J=8.5Hz); 7.24 (d, 2H, J=8.0 Hz); 6.74 (dd, 1H, J=8.0 Hz, J=2.0 Hz);6.72-6.68 (m, 2H), 4.42 (t, 2H, J=13.0 Hz); 3.86 (m as t, 4H, J=5.0 Hz);3.10 (m as t, 4H, J=5.0 Hz), 3.08 (t, 1H, J=6.8 Hz), 2.95 (t, 1H, J=6.8Hz); 2.75 (tt, 1H, J=12.0 Hz, J=3.5 Hz); 1.94 (d, 2H, J=13.0 Hz); 2.75(qd, 1H, J=13.0 Hz, J=4.0 Hz)

Example 71: 3-(1,1-Dioxidothiomorpholino)phenyl4-(3-phenoxybenzyl)piperazine-1-carboxylate

¹H NMR (500 MHz, CDCl₃) δ 7.54 (t, 2H, J=8.0 Hz); 7.32 (t, 2H, J=8.5Hz); 7.24-6.90 (m, 4H); 6.74 (dd, 1H, J=8.0 Hz, J=2.0 Hz); 6.65-6.61 (m,2H), 4.42 (t, 2H, J=13.0 Hz); 3.86 (m as t, 4H, J=5.0 Hz); 3.10 (m as t,4H, J=5.0 Hz), 3.08 (t, 1H, J=6.8 Hz), 2.95 (t, 1H, J=6.8 Hz); 2.75 (tt,1H, J=12.0 Hz, J=3.5 Hz); 1.94 (d, 2H, J=13.0 Hz); 2.75 (qd, 1H, J=13.0Hz, J=4.0 Hz)

Example 72: 3-(1,1-Dioxidothiomorpholino)phenyl4-(quinolin-2-ylmethyl)piperazine-1-carboxylate

¹H NMR (500 MHz, CDCl₃) δ 7.44 (t, 2H, J=8.0 Hz); 7.28 (t, 2H, J=8.5Hz); 7.24 (d, 2H, J=8.0 Hz); 6.74 (dd, 1H, J=8.0 Hz, J=2.0 Hz);6.72-6.68 (m, 2H), 4.42 (t, 2H, J=13.0 Hz); 3.86 (m, 4H,); 3.10 (m as t,4H, J=5.0 Hz), 3.08 (t, 1H, J=6.8 Hz), 2.95 (t, 1H, J=6.8 Hz); 2.75 (tt,1H, J=12.0 Hz, J=3.5 Hz); 1.94 (d, 2H, J=13.0 Hz); 2.73 (qd, 2H, J=13.0Hz, J=4.0 Hz)

Example 73: 3-(1,1-Dioxidothiomorpholino)phenyl2-methyl-4-phenylpiperazine-1-carboxylate

¹H NMR (500 MHz, CDCl₃) δ 7.34 (t, 2H, J=8.0 Hz); 7.26 (t, 2H, J=8.5Hz); 7.24 (d, 2H, J=8.0 Hz); 6.74 (dd, 1H, J=8.0 Hz, J=2.0 Hz);6.70-6.48 (m, 2H), 4.42 (t, 2H, J=13.0 Hz); 3.86 (m as t, 4H, J=5.0 Hz);3.10 (m as t, 4H, J=5.0 Hz), 3.08 (t, 1H, J=6.8 Hz), 2.95 (t, 1H, J=6.8Hz); 2.75 (tt, 1H, J=12.0 Hz, J=3.5 Hz); 1.94 (d, 2H, J=13.0 Hz); 1.56(d, 2H, J=8 Hz)

Method H Syntheses of Azetidine Carbamates 40

As depicted in Scheme VIII, syntheses of azetidine carbamates 40 involvecoupling chloroformates 16 (Scheme III) with azetidine derivatives 39.Substituted azetidine derivatives 39 were obtained in two steps fromcommercially available 1-benzhydrylazetidin-3-ol (37). This processinvolves displacement of 4-chlorobenzyl bromide with 37 to producebenzylazetidine ether 38 followed by removal of benzhydryl protection togive substituted azetidine 39 (Hart et al Biorg. & Med. Chem. Lett.(2009) 19: 4241-4244).

The Following Examples were Prepared by Following Method H

Synthesis of Example 74 3-Cyanophenyl3-(4-chlorobenzyloxy)azetidine-1-carboxylate Step a) Synthesis of1-Benzhydryl-3-(4-chlorobenzyloxy)azetidine (38, R₁=Cl)

A solution of 4-chlorobenzyl bromide (3.1 g, 15.0 mmol) in THF (20 mL)was added to a suspension of 1-benzhydrylazetidin-3-ol sodium salt,which was generated in-situ by treating azetidinol 37 (2.4 g, 10.0 mmol)in dry THF (100 mL) at 0° C. with NaH (60% dispersion in mineral oil,410 mg, 10.5 mmol). The resulting mixture was refluxed for 6 hours,cooled to room temperature, and diluted with water. The aqueous layerwas extracted with EtOAc and the organic layer was washed with brine,dried over MgSO₄ and solvent removed in vacuo. The crude product waspurified by column chromatography on silica gel to give 2.77 g of1-Benzhydryl-3-(4-Chlorobenzyloxy) azetidine as viscous liquid. H NMR(400 MHz, CDCl₃) δ 7.38-7.33 (m, 3H); 7.32-7.20 (m, 11H); 4.36 (s, 2H);4.2-4.18 (m, 1H); 3.55-3.45 (m, 2H); 3.0-2.90 (m, 2H)

Step b) Synthesis of 3-(4-chlorobenzyloxy)azetidine (39, R₁=Cl)

A solution of 1-benzhydryl-3-(4-chlorobenzyloxy)azetidine (38, 2.55 g,7.0 mmol) in anhydrous dichloromethane (50 mL) was treated with1-chloroethyl chloroformate (2.70 mL, 24.5 mmol) at room temperature andstirred for 1 h. The mixture was treated with methanol (10 mL) andstirred at the same temperature for additional 6 h. The solvent wasremoved under reduced pressure and the residue was triturated with 5%ethyl acetate:hexane to give azetidine hydrochloride salt, which waspartitioned between dichloromethane and aqueous NaHCO₃. The aqueouslayer was further extracted with dichloromethane. The combined organiclayer was washed with brine, dried over MgSO₄ and solvent removed invacuo to give a 1.26 g of 3-(4-chlorobenzyloxy)azetidine (39) as paleyellow gum.

¹H NMR (400 MHz, CDCl₃) δ 7.31 (d, 2H, J=8.0 Hz)); δ 7.31 (d, 2H, J=8.0Hz)); 7.28 (d, 2H, J=8.0 Hz)); 4.35 (s, 2H); 4.22-4.17 (m, 1H);3.55-3.45 (m, 2H); 3.0-2.90 (m, 2H)

Step b) Synthesis of 3-Cyanophenyl3-(4-chlorobenzyloxy)azetidine-1-carboxylate

To a stirred solution of 3-cyanophenyl chloroformate 16 (Scheme III,0.36 g, 2.0 mmol) in methylene chloride (20 mL) at room temperatureunder argon atmosphere were added a 3-(4-chlorobenzyloxy)azetidine (39)(Scheme VIII, 0.5 g, 2.50 mmol) and triethylamine (0.35 mL, 2.5 mmol)and the resulting mixture was stirred at room temperature for 2 hours.After the completion of reaction, as monitored by TLC, the mixture wasdiluted with water, the aqueous layer was extracted with methylenechloride (2×10 mL), and the combined organic layer was dried over MgSO₄.The solvent was removed under reduced pressure to give a crude material,which was purified by column chromatography on silica gel to afford 0.45g of 3-cyanophenyl 3-(4-chlorobenzyloxy)azetidine-1-carboxylate as whitesolid.

¹H NMR (400 MHz, CDCl₃) δ: 7.47-7.42 (m, 2H); 7.38 (d, 1H, J=8.0 Hz);7.36 (d, 2H, J=8.0 Hz); 7.33-7.25 (m, 3); 4.47 (s, 2H); 4.46-4.39 (m,1H); 4.38-4.18 (m, 2H); 4.17-3.98 (m, 2H)

Examples 75-80 were Synthesized by Method H

Example 75: 3-(Trifluoromethyl)phenyl3-(4-chlorobenzyloxy)azetidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ: 7.31 (d, 2H, J=8.0 Hz); 7.28-7.22 (m, 4H);7.17 (t, 1H, J=8.0 Hz); 7.02 (d, 1H, J=8.0 Hz); 4.46 (s, 2H); 4.44-4.34(m, 1H); 4.32-4.13 (m, 2H); 4.12-3.94 (m, 2H)

Example 76: 3-Bromophenyl 3-(4-chlorobenzyloxy)azetidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ: 7.31 (d, 2H, J=8.0 Hz); 7.28-7.22 (m, 4H);7.17 (t, 1H, J=8.0 Hz); 7.02 (d, 1H, J=8.0 Hz); 4.46 (s, 2H); 4.44-4.34(m, 1H); 4.32-4.13 (m, 2H); 4.12-3.94 (m, 2H)

Example 77: 3-Carbamoylphenyl3-(4-chlorobenzyloxy)azetidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ: 7.62 (d, 1H, J=8.0 Hz); 7.56 (m, 1H); 7.43(t, 1H, J=8.0 Hz); 7.34 (d, 2H, J=8.0 Hz); 7.28 (d, 2H, J=8); 7.25-7.22(m, 1H); 6.08 (brs, 1H); 5.06 (brs, 1H); 4.46 (s, 2H); 4.45-4.40 (m,1H); 4.38-4.18 (m, 2H); 4.15-3.95 (m, 2H)

Example 78: 3-Methoxyphenyl 3-(4-Bromobenzyloxy)azetidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ: 7.51 (d, 1H, J=8.0 Hz); 7.25 (d, 2H, J=8.0Hz); 7.23 (dt, 2H, J=8.0 Hz, J=2.0 Hz); 6.74 (dd, 1H, J=8.0 Hz, J=2.0Hz); 6.70 (dd, 1H, J=8.0 Hz, J=2.0 Hz); 6.66 (t, 1H, J=2.0 Hz); 4.48 (s,2H); 4.47-4.38 (m, 1H); 4.39-4.29 (m, 2H); 4.26-4.04 (m, 2H); 3.78 (s,3H)

Example 79: 2,4-Dichlorophenyl3-(4-chlorobenzyloxy)azetidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ: 7.42 (d, 1H, J=2.0 Hz); 7.35 (d, 2H, J=8.0Hz); 7.28 (d, 2H, J=8.0 Hz); 7.23 (dd, 1H, J=8.0 Hz, J=2.0 Hz); 7.14 (d,1H, J=8.0 Hz); 4.48 (s, 2H); 4.47-4.36 (m, 2H); 4.28-4.14 (m, 2H);4.08-3.88 (m, 2H)

Example 80: 3-(Pyridin-3-yl)phenyl3-(4-chlorobenzyloxy)azetidine-1-carboxylate

¹H NMR (400 MHz, CDCl₃) δ: 8.12 (d, 1H, J=8.0 Hz); 7.68 (d, 1H, J=8.0Hz); 7.65 (d, 1H, J=8.0 Hz); 7.57-7.51 (m, 2H); 7.50-7.40 (m, 2H); 7.35(2H, J=8.0 Hz); 7.29 (d, 2H, J=8.0 Hz); 7.22 (1H, J=8.0 Hz); 4.48 (s,2H); 4.47-4.40 (m, 1H); 4.38-4.20 (m, 2H); 4.20-4.0 (m, 2H)

Method I Syntheses of Azetidine Carboxamides 42

As depicted in Scheme IX, azetidine carboxamides 42 were obtained bycoupling commercially available isocyanates 41 with3-(4-chlorobenzyloxy)azetidine or 3-(4-bromobenzyloxy)azetidine 39(Scheme VIII).

Synthesis of Example 813-(4-Chlorobenzyloxy)-N-phenylazetidine-1-carboxamide Step a)

To a stirred solution of commercially available phenyl isocyanate (60 mg0.5 mmol) in methylene chloride (20 mL) at room temperature under argonatmosphere were added a 3-(4-chlorobenzyloxy)azetidine (39) (SchemeVIII, 120 mg, 0.60 mmol) and triethylamine (0.08 mL, 2.5 mmol) and theresulting mixture was stirred at room temperature for 4 hours. After thecompletion of reaction, as monitored by TLC, the mixture was dilutedwith water, the aqueous layer was extracted with methylene chloride(2×10 mL), and the combined organic layer was dried over MgSO₄. Thesolvent was removed under reduced pressure to give a crude material,which was purified by column chromatography on silica gel to afford 135mg 3-(4-chlorobenzyloxy)-N-phenylazetidine-1-carboxamide as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ: 7.37 (d, 2H, J=8.0 Hz); 7.34 (d, 2H, J=8.0Hz); 7.30-7.25 (m, 4H); 7.03 (t, 1H, J=8.0 Hz); 5.94 (brs, 1H); 4.45 (s,2H); 4.42-4.36 (m, 1); 4.17 (dd, 2H, J=9.2 Hz, J=4.0 Hz); 3.96 (dd, 1H,J=9.2 Hz, J=4.0 Hz)

Example 82 was Synthesized by Method H Example 82:3-(4-Bromobenzyloxy)-N-(pyridin-3-yl)azetidine-1-carboxamide

¹H NMR (400 MHz, CDCl₃) δ: 8.60 (t, 2H, J=2.0 Hz); 8.50 (brs, 1H, >NH);8.08 (d, 1H, J=8.0 Hz); 7.88 (dd, 1H, J=8.0 Hz, J=2.0 Hz); 7.45 (d, 2H,J=7.6 Hz); 7.24 (d, 2H, J=7.6 Hz); 7.13 (dd, 1H, J=8.0 Hz, J=4.0 Hz);4.40 (s, 2H); 4.39-4.31 (m, 1H); 4.13 (t, 2H, J=9.2 Hz); 3.82 (dd, 1H,J=9.2 Hz, J=4.0 Hz)

Method J Syntheses of Azetidine Methanones 47

As depicted in Scheme X, azetidine methanones 47 were produced bycoupling azetidine carbonyl chlorides 46 with commercially available4-phenyl-1H-imidazole, 1H-1,2,3-triazole or 1H-benzo[d]imidazole.Azetidine carbonyl chlorides 46 were obtained in two steps includingdisplacement of commercially available benzhydrlyazetidine mesylate 43with commercially available 4-phenylpiperidine or 4-thiophenol, to give3-aminoazetidine or azetidine thioether 44. Subsequently, deprotectionof benzhydryl group gave azetidine derivative 45, which werecarbonylated with triphosgene.

The Following Examples were Prepared by Following Method J

Synthesis of Example 83(1H-Benzo[d]imidazol-1-yl)(3-(4-phenylpiperidin-1-yl)azetidin-1-yl)methanoneStep a) Syntheses of 1-(Benzhydrylazetidin-3-yl)-4-phenylpiperidine 44(R₁ is 4-phenylpiperidine)

To a solution of 43 (3.2 g, 10.0 mmol) in acetonitrile (50 mL)) wereadded 4-phenylpiperidine (1.93 g, 12.0 mmol) and diisopropylethyl amine(2.1 mL, 12.0 mmol), sequentially and the mixture heated at 70° C. for 3h. Solvent was removed under reduced pressure, and the resulting slurrypartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried over MgSO₄ and evaporated. The crude productwas purified by column chromatography on silica gel to give 2.75 g of1(1-benzhydrylazetidin-3-yl)-4-phenylpiperidine as white solid.

¹H NMR (400 MHz, CDCl₃) δ: 7.39 (d, 4H, J=9.0 Hz) 7.27 (d, 6H, J=9.0Hz); 7.21-715 (m, 3H); 7.12 (d, 2H, J=9.0 Hz); 4.4 (s, 1H), 3.35-3.25(m, 2H); 3.0-2.85 (m, 3H); 2.8-2.7 (m, 3H); 1.80-1.65 (m, 2H); 1.69 (d,2H, J=13.0 Hz); 1.35-1.25 (m, 2H)

Step b) Synthesis of 1-(azetidin-3-yl)-4-phenylpiperidine 45 (R₁ is4-phenylpiperidine)

A solution of 1-(benzhydrylazetidin-3-yl)-4-phenylpiperidine (1.91 g,5.0 mmol) in anhydrous dichloromethane (20 mL) was treated with1-chloroethyl chloroformate (1.91 mL, 17.5 mmol) at room temperature andstirred for 1 h. The mixture was treated with methanol (5 mL) andstirred at the same temperature for additional 6 h. The solvent wasremoved under reduced pressure and the residue was washed with 5% ethylacetate: hexane to give a partially purified azetidine hydrochloridesalt, which alt was partitioned between dichloromethane and aqueousNaHCO₃. The organic layer was washed with brine, dried over MgSO₄ andsolvent removed in vacuo to give a 0.99 g of1-(azetidin-3-yl)-4-phenylpiperidine as pale yellow gum

¹H NMR (400 MHz, CDCl₃) δ: 7.31 (d, 2H, J=8.0 Hz); 7.27-7.20 (m, 3H);3.33-3.23 (m, 2H); 3.10-2.90 (m, 3H); 2.82-2.72 (m, 3H); 2.1 (brs 1H);1.81-1.64 (m, 2H); 1.69 (d, 2H, J=13.0 Hz); 1.33-1.23 (m, 2H)

Step c) Synthesis of 1-(4-phenylpiperidine-1-yl)azetidin-1-carbonylchloride 46 (R₁ is 4-phenylpiperidine)

To a solution of triphosgene (0.45 g, 1.5 mmol) in dichloromethane (10mL) at 0° C. under nitrogen atmosphere was added a solution of1-(azetidin-3-yl)-4-phenylpiperidine (0.97 g, 4.5 mmol) and pyridine(0.45 mL, 4.5 mmol) in dichloromethane (10 mL) drop-wise over 10minutes. The mixture was stirred at room temperature for 1 hour anddiluted with ice-cold water (10 ml). The organic layer was washed withbrine, dried over MgSO₄ and solvent removed in vacuo to give a 0.96 g of1-(4-phenylpiperidine-1-yl)azetidin-1-carbonyl chloride as white solid.

¹H NMR (400 MHz, CDCl₃) δ: 7.31 (d, 2H, J=8.0 Hz); 7.27-7.20 (m, 3H);4.25-3.95 (m, 4H); 3.30-3.20 (m, 1H); 3.0-2.85 (m, 2H); 2.60-2.50 9m,1H); 2.10-2.1.95 (m, 2H); 1.94-1.80 (4H).

Step d) Synthesis of(1H-Benzol[d]imidazol-1-yl)(3-(4-phenylpiperidin-1-yl)azetidin-1-yl)methanone

To a solution of 1-(4-phenylpiperidine-1-yl)azetidin-1-carbonyl chloride(280 mg, 1.0 mmol) in dichloromethane (20 mL) at room temperature wasadded 1H-Benzo[d]imidazole (177 mg, 1.5 mmol) and triethylamine (0.22ml, 1.5 mmol). The mixture stirred for 6 hours and diluted with water(10 ml). The organic layer was washed with brine, dried over MgSO₄ andsolvent removed in vacuo. The crude material was purified by columnchromatography on silica gel to give 0.26 g of(1H-Benzo[d]imidazol-1-yl)(3-(4-phenylpiperidin-1-yl)azetidin-1-yl)methanoneas white solid.

¹H NMR (400 MHz, CDCl₃) δ: 8.20 (s, 1H); 7.95 (d, 1H, J=8.0 Hz); 7.80(d, 1H, J=8.0 Hz); 7.41 (t, 1H, J=8.0 Hz); 7.38 (t, 1H, J=8.0 Hz); 7.32(t, 2H, J=8.0 Hz); 7.25-7.19 (m, 3H); 4.5-4.35 (m, 4H); 4.32-4.24 (m,2H); 3.55-3.35 (m, 1H); 3.2-2.9 (m, 2H); 2.70-2.50 (m, 1H); 2.20-1.80(m, 4H)

Examples 84-91 were Synthesized by Method J

Example 84(3-(4-Benzylpiperidine)azetidin-1-yl)(4-phenyl[1H]imizadol-1-yl)methanone

¹H NMR (400 MHz, CDCl₃) 8.00 (s, 1H); 7.78 (d, 2H, J=7.2 Hz); 7.54 (s,1H); 7.39 (t, 2H, J=8.0 Hz); 7.28 (t, 3H, J=8. Hz); 7.20 (t, 1H, J=7.20Hz); 7.14 (d, 2H, J=7.2 Hz); 4.40-4.42 (m, 4H); 3.34-3.24 (m, 1H);2.95-2.87 (m, 2H); 2.56 (d, 2H, J=6.8 Hz); 1.73 (d, 2H, J=11.0 Hz),1.65-1.54 (m, 3H); 1.46-1.34 (m, 2H)

Example 85(4-Phenyl-1H-imidazol-1-yl)(3-(4-phenylpiperidin-1-yl)azetidin-1-yl)methanone

¹H NMR (400 MHz, CDCl₃) 8.03 (s, 1H); 7.80 (d, 2H, J=7.2 Hz); 7.57 (s,1H); 7.40 (t, 2H, J=7.2 Hz); 7.31 (d, 2H, J=7.20 Hz) overlapping with(m, 1H); 7.23 (t, 2H, J=7.20 Hz) overlapping with (m, 1H); 4.45-4.35 (m,2H); 4.34-4.4.25 (m, 2H); 3.4-3.30 (m, 1H); 3.0 (d, 2H, J=9.2 Hz); 2.56(t, 1H, J=9.2 Hz); 2.19 (t, 2H, J=9.2 Hz); 1.91-1.78 (m, 4H)

Example 86(3-(4-Bromobenzyloxy)azetidin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone

¹H NMR (400 MHz, CDCl₃) 8.27 (s, 1H); 7.82 (d, 2H, J=7.6 Hz); 7.58 (s,1H); 7.50 (d, 2H, J=8.0 Hz); 7.42 (t, 2H, J=7.6 Hz, J=2.0 Hz); 7.35 (t,1H, J=8.0 Hz); 4.57-4.48 (m, 3H); 4.45 (s, 2H); 4.32-4.26 (m, 2H)

Example 87(1H-Benzo[d]imidazol-1-yl)(3-(4-Bromobenzyloxy)azetidin-1-yl)methanone

¹H NMR (400 MHz, CDCl₃) 8.50 (s, 1H); 7.85 (d, 2H, J=7.2 Hz); 7.84 (d,2H, J=7.2 Hz); 7.46 (td, 1H, J=8.0 Hz, J=2.0 Hz); 7.397 (td, 1H, J=8.0Hz, J=2.0 Hz); 7.21 (d, 2H, J=8.0 Hz); 4.55-4.48 (m, 3H); 4.46 (s, 2H);4.29-4.23 (m, 2H)

Example 88 3-(4-Bromobenzyloxy)azetidin-1-yl](piperidin-1-yl)methanone

¹H NMR (400 MHz, CDCl₃) 7.33 (d, 2H, J=7.6 Hz); 7.29-7.23 (m, 4H); 6.91(d, 2H, J=7.2); 4.43 (s, 2H); 4.35-4.18 (m, 1); 4.14 (t, 2H, J=9.0 Hz);3.93 (dd, 2H, J=9.0 Hz, J=4.0 Hz); 3.48 (t, 4H, J=4.80 Hz); 3.14 (t, 4H,J=4.80 Hz)

Example 89(3-(4-Phenylpiperidin-1-yl)azetidin-1-yl)(1H-pyrazol-1-yl)methanone

¹H NMR (400 MHz, CDCl₃) 8.20 (s, 1H); 7.62 (s, 1H); 7.33 (t, 2H, J=8.0Hz); 7.26 (t, 1H, J=8.0 Hz); 7.23 (d, 2H, J=8.0 Hz); 6.4 (s, 1H);5.20-5.05 (m, 1H); 4.95-4.85 (m, 1H); 4.80-4.65 (m, 1H); 4.55-4.35 (m,1H); 3.95-3.85 (m, 1H); 3.70-3.55 (m, 2H); 2.75-2.55 (m, 3H); 2.40 (q,2H, J=12.0 Hz), 2.1 (d, 2H, J=12.0 Hz

Example 903-(4-Phenylpiperidin-1-yl)azetidin-1-yl)(1H-1,2,4-triazol-1-yl)methanone

¹H NMR (400 MHz, CDCl₃) 8.87 (d, 1H, J=3.2 Hz); 7.97 (d, 2H, J=3.2 Hz);7.34-7.28 (m, 2H); 7.25-7.18 (m, 3H); 4.80-4.70 (m, 1H); 4.64-4.50 (m,1H); 4.35-4.23 (m, 1H); 4.22-4.08 (m, 1H); 3.35-3.20 (m, 1H); 3.10-2.85(m, 2H); 2.54 (t, 1H, J=12.0 Hz); 2.12-1.98 (m, 2H), 1.95-1.75 (m, 4H)

Example 913-(4-Bromophenylthio)azetidin-1-yl)(1H-1,2,4-triazol-1-yl)methanone

¹H NMR (400 MHz, CDCl₃) 8.88 (s, 1H) 7.97 (s, 1H); 7.45 (d, 2H, J=7.6Hz); 7.16 (d, 2H, J=7.6 Hz); 5.15-5.0 (m, 1H); 4.70-4.50 (m, 2H);4.20-4.15 (m, 2H)

Method K: Synthesis of N-Aryl Bridged Piperazine Urea Derivatives 51

Referring to Scheme XI, N-Aryl urea derivatives 51 were synthesized byreaction of bridged piperazine derivatives 50 with substituted biarylphenyl carbamates 6 (scheme I), under microwave irradiation. Bridgedpiperazine derivatives 50 were obtained by deprotection of N-BOC group49 under acidic condition. Which in turn were prepared by nucleophilicdisplacement of benzylic bromides with commercially availablesubstituted N—BOC bridged piperazine 48.

The Following Examples were Prepared by Following Method K

Synthesis of Example 92:(1S,4S)—N-(3-Bromophenyl)-5-(quinolin-2-ylmethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (A₁=Quinolin-2-yl, R₃=CONH₂) Step a) Synthesis ofTert-Butyl(1S,4S)-5-(quinolin-2-ylmethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate49 (A₁=Quinolin-2-yl)

To a solution of 2-(chloromethyl)quinoline hydrobromide (2.0 g, 7.74mmol) in acetonitrile (20 mL) was added tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate 48, (1.86 g, 9.28mmol) and triethylamine (1.61 mL, 16.1 mmol) and the resulting mixturewas heated in a sealed tube under microwave irradiation at 100° C. for15 min with stirring. The reaction mixture was cooled to roomtemperature. The solvent was removed in vacuo and the residuepartitioned between dichloromethane and water. The aqueous layer wasfurther extracted with dichloromethane and the combined organic extractswere washed with brine, and dried over MgSO₄. The solvent was removed invacuo to give a crude product, which was purified by flash columnchromatography to give 2.25 g of tert-butyl(1S,4S)-5-(quinolin-2-ylmethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as colorless oil.

¹H NMR (500 M Hz, CDCl₃) 8.09 (d, 1H, J=9 Hz); 8.06 (d, 1H, J=9.0 Hz);7.81 (d, 1H, J=8.0 Hz); 7-71-7.66 (m, 2H); 7.51 (t, 1H, J=8.0 Hz); 7.13(bd, 1H, J=9.0 Hz) 7.06 (bd, 1H, J=9.0 Hz); 4.25 (d, 1H, J=14 Hz);3.84-3.65 (m, 3H); 3.15 (bs, 1H); 2.93 (bs, 1H); 2.70 (brs, 1H); 2.58(brs, 1H); 0.96 (brs, 9H)

Step b) Synthesis of2-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)quinoline

To a solution of tert-butyl(1S,4S)-5-(quinolin-2-ylmethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(2.0 g, 5.86 mmol) in methylene chloride (25 mL) was addedtrifluoroacetic acid (2.2 mL, 29.3 mmol). After stirring at roomtemperature for 16 h, the mixture was concentrated in vacuo, and residuewas partitioned between ethyl acetate and aqueous sodium bicarbonate.The aqueous layer was extracted with Ethyl acetate and the combinedorganic layer was washed with water (20 mL) brine (20 mL), and driedover MgSO₄. The solvent was removed in vacuo to give2-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)quinolone (1.27 g)which was used for next reaction without further purification.

¹H NMR (500 M Hz, CDCl₃) δ 8.13 (d, 1H, J=9 Hz); 8.06 (d, 1H, J=9.0 Hz);7.81 (d, 1H, J=8.0 Hz); 7-71-7.66 (m, 2H); 7.51 (t, 1H, J=8.0 Hz); 7.14(bd, 1H, J=9.0 Hz) 7.05 (bd, 1H, J=9.0 Hz); 4.25 (d, 1H, J=14 Hz);3.84-3.65 (m, 3H); 3.15 (brs, 1H); 2.93 (brs, 1H); 2.70 (brs, 1H); 2.58(brs, 1H

Step c) Synthesis of(1S,4S)—N-(3-bromophenyl)-5-(quinolin-2-ylmethyl)-2,5-diazabicyclo[2.2.1] heptane-2-carboxamide

A solution of2-(((1S,4S)-2,5-diazabicyclo[0.2.1]heptan-2-yl)methyl)quinoline (0.5 g,2.34 mmol) and biphenyl-3-yl-carbamic acid phenyl ester 6 (0.92 g, 2.77mmol) in acetonitrile (10 mL) was heated in a sealed tube undermicrowave irradiation at 120° C. for 10 min with stirring. The reactionmixture was cooled to room temperature and solvent was removed underreduced pressure. The crude material was partitioned betweendichloromethane and water. The aqueous phase was extracted withdichloromethane. The combined organic extracts was washed with water (10mL), brine (10 mL) and dried over MgSO₄. The solvent was removed invacuo to give residue which was chromatographed to give 0.60 g of(1S,4S)—N-(3-bromophenyl)-5-(quinolin-2-ylmethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide,as white solid.

¹H NMR (500 M Hz, CDCl₃) δ 8.16 (d, 1H, J=7 Hz); 8.02 (d, 1H, J=7 Hz);8.01 (s, 1H); 7.81 (d, 1H, J=7 Hz); 7.68-7.73 (m, 3H); 7.65 (d, 1H, J=5Hz); 7.58-7.52 (m, 2H); 7.41-7.46 (m, 2H); 7.32 (t, 1H, J=7.5 Hz); 7.21(d, 1H, J=7.5 Hz); 6.99 (s, 1H); 6.45 (brs, 1H); 6.48 (brs, 1H); 4.24(d, 1H, J=12 Hz); 3.86 (d, 1H, J=13 Hz); 3.74 (td, 1H, J=12.5 Hz); 3.63(d, 1H, J=14 Hz); 3.24 (td, 1H, J=10 Hz, J=3 Hz); 3.03 (dd, 1H, J=13 Hz,J=9 Hz); 2.77 (dt, 1H, J=12 Hz, J=4.0 Hz); 2.64-2.59 (m, 1H); 2.36 (t,J=12.5 Hz, J=3.0 Hz); 1.19 (d, 3H, J=6.5 Hz)

Examples 93-95 were Prepared According to Method K

Example 93:(1S,4S)—N-(3′-cyano-[1,1′-biphenyl]-3-yl)-5-(quinolin-2-ylmethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide

¹H-NMR: CDCl3 δ: 8.12 (d, 1H, J=8 Hz), 8.06 (d, 1H, J=8 Hz), 7.92 (s,1H), 7.82 (d, 2H, J=8 Hz), 7.71-7.69 (m, 2H), 7.67 (d, 1H, J=8.5 Hz),7.61 (td, 1H), 7.55-7.49 (m, 2H), 7.37 (t, 1H, J=8 Hz), 7.30 (dd, 1H,J=1.5 Hz, J2=8 Hz), 7.24 (td, 1H), 6.45 (s, 1H), 4.29 (d, 1H, J=14 Hz),3.84 (td, 1H), 3.72 (t, 1H, J=8.5 Hz), 3.68 (d, 1H, J=14.5 Hz), 3.29(td, 1H), 3.06 (dd, 1H, J=9 Hz, J=13 Hz), 2.83 (td, 1H, J=8.5 Hz),2.73-2.67 (m, 1H), 2.43 (td, 1H), 1.24 (d, 3H, J=6.5 Hz)

Example 94:(1S,4S)-5-([1,1′-biphenyl]-3-ylmethyl)-N-(3′-cyano-[1,1′-biphenyl]-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide

¹H-NMR: CDCl3 δ: 8.14 (d, 1H, J=8 Hz), 7.96 (d, 1H, J=8 Hz), 7.92 (s,1H), 7.83 (d, 2H, J=8 Hz), 7.70-7.67 (m, 2H), 7.65 (d, 1H, J=8.5 Hz),7.59 (td, 1H), 7.55-7.49 (m, 2H), 7.37 (t, 1H, J=8 Hz), 7.28 (dd, 1H,J1=1.5 Hz, J2=8 Hz), 7.24 (s, 1H), 6.45 (s, 1H), 4.29 (d, 1H, J=14 Hz),3.84 (td, 1H), 3.72 (t, 1H, J=8.5 Hz), 3.68 (d, 1H, J=14.5 Hz), 3.29(td, 1H), 3.06 (dd, 1H, J=9 Hz, J=13 Hz), 2.81 (d, 1H, J=8.5 Hz),2.72-2.67 (m, 1H), 2.43 (d, 1H, J=4.5 Hz), 1.22 (d, 3H, J=6.5 Hz)

Example 95:(1S,4S)—N-(3-bromophenyl)-5-(quinolin-2-ylmethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide

¹H-NMR: CDCl3 δ: 8.04 (d, 1H, J=8 Hz), 7.98 (d, 1H, J=8 Hz), 7.92 (s,1H), 7.81 (d, 2H, J=8 Hz), 7.71-7.69 (m, 2H), 7.65 (d, 1H, J=8.5 Hz),7.61 (td, 1H), 7.55-7.49 (m, 2H), 7.37 (t, 1H, J=8 Hz), 7.30 (dd, 1H,J1=1.5 Hz, J2=8 Hz), 7.24 (td, 1H), 6.45 (s, 1H), 4.29 (d, 1H, J=14 Hz),3.84 (td, 1H), 3.72 (t, 1H, J=8.5 Hz), 3.68 (d, 1H, J=14.5 Hz), 3.29(td, 1H), 3.06 (dd, 1H, J=9 Hz, J=13 Hz), 2.83 (td, 1H, J=8.5 Hz),2.72-2.67 (m, 1H), 2.43 (td, 1H), 1.22 (d, 3H, J=6.5 Hz)

Method L: Synthesis of Imidazolyl Ureas 56 and 57.

Imidazolyl ureas 56 and 57 (Scheme XII) were synthesized by reaction ofbridged piperazine derivatives 50 (Scheme XI) or 55 with 4-nitrophenyl4-phenyl-1H-imidazole-1-carboxylate 9 (Scheme II) in dichloromethane.Intermediate bridged piperazine 55 was synthesized by N-arylation ofcommercially available tert-butyl(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate 48 with arylbromides under the Buchwald coupling condition (Bermejo et al, J. Am.Chem. Soc., (2008) 130: 15798-15799), followed by deprotection of N-BOCgroup under acidic condition.

The Following Examples were Prepared by Following Method L

Synthesis of Example 96,(4-Phenyl-1H-imidazol-1-yl)((1S,4S)-5-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methanone Step a) Synthesis of Tert-Butyl(1S,4S)-5-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(54: A₃=pyridin-2-yl)

A degassed mixture of commercially available 2-bromopyridine (0.72 g,1.5 mmol), tert-butyl(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (162 mg, 1.5 mmol)48, BINAP (124 mg, 0.08 mmol), Pd₂dba₃ (156 mg, 0.05 mmol), and sodiumtert-butoxide (1.54 g, 1.55 mmol), in 1,2-dimethoxy ethane was heated ina sealed tube at 120° C. for 12 h. The reaction mixture was poured intowater (15 mL) and extracted with ethyl acetate (2×30 mL). The combinedorganic layer was washed with water (20 mL) and brine (20 mL), driedover MgSO4 and evaporated. Further purification of crude material byflash chromatography on silica gel gave tert-butyl(1S,4S)-5-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(0.58 g) as light yellow liquid.

¹H NMR (500 M Hz, CDCl₃) δ 8.13 (d, 1H, J=9 Hz); 8.06 (d, 1H, J=9.0 Hz);7.81 (d, 1H, J=8.0 Hz); 7-71-7.66 (m, 2H); 7.51 (t, 1H, J=8.0 Hz); 7.23(bd, 1H, J=9.0 Hz) 7.05 (bd, 1H, J=9.0 Hz); 4.25 (d, 1H, J=14 Hz);3.84-3.65 (m, 3H); 3.15 (brs, 1H); 2.93 (brs, 1H); 2.70 (brs, 1H); 2.58(brs, 1H)

Step b) Synthesis of(1S,4S)-2-(Pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane (55:A₃=pyridin-2-yl)

To a solution of tert-butyl(1S,4S)-5-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate(1.5 g, 5.86 mmol) in methylene chloride (25 mL) was addedtrifluoroacetic acid (2.25 mL, 29.3 mmol). After stirring at roomtemperature for 16 h, the mixture was concentrated in vacuo, and dilutedwith ethyl acetate and aqueous sodium bicarbonate. The organic layer waswashed with water (10 mL), brine (10 mL), dried over MgSO₄. The solventwas removed in vacuo to give to give1S,4S)-2-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane (1.01 g) whichwas used in the next step without further purification.

Step c) Synthesis of(4-phenyl-1H-imidazol-1-yl)((1S,4S)-5-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methanone

To a solution of (1S,4S)-2-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane(0.7 g, 3.17 mmol) in dichloromethane was added4-phenylimidazole-4-nitrophenyl carboxylate (1.21 g, 3.64 mmol) 9(scheme II) and mixture was stirred at room temperature for 2 hours.Solvent was removed under reduced pressure. The residue waschromatographed over silica gel to give(4-phenyl-1H-imidazol-1-yl)((1S,4S)-5-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methanone(1.21 g) as white solid.

1H NMR (500 MHz, CDCl3) δ 7.98 (s, 1H); 7.81 (d, 2H, J=8.0 Hz); 7.53 (s,1H); 7.41 (t, 2H, J=7.5 Hz); 7.34 (dt, 1H, J=8.0 Hz, J=2.0 Hz);7.11-6.92 (m, 5H, J=8.0 Hz); 6.88-6.81 (m, 4H); 3.97 (dt, 1H, J=13.0 Hz,J=4.5 Hz); 3.85 (dd, 1H, J=13.0 Hz, J=2.0 Hz); 3.72-3.6 (m, 3H); 3.19(qd, 2H, J=13.0, J=3.5 Hz); 2.30 (s, 3H), 1.03 (d, 3H, J=6.0 Hz).

Examples 97-100 were Prepared According to Method B

Example 97:((1S,4S)-5-(3-Fluorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(4-phenyl-1H-imidazol-1-yl)methanone

¹H NMR (500 MHz, CDCl₃) δ 7.89 (d, 1H, J=7.5 Hz); 7.77 (d, 1H, J=2.0Hz); 7.53 (t, 1H, J=8.0 Hz), 7.18 (d, 1H, J=1.0 Hz); 7.06 (t, 1H, J=7.5Hz, J=1.0 Hz); 7.01 (d, 1H, J=8.0 Hz); 3.96 (d, 2H, J=13.0 Hz), 3.54(dt, 2H, J=13.0 Hz, J=2.0 Hz); 2.77 (s, 2H); 2.20 (d, 2H, J=13.0 Hz),1.74 (dt, 2H, J=13.5 Hz, J=5.0 Hz).

Example 98:((1S,4S)-5-(3-(Benzyloxy)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(4-phenyl-1H-imidazol-1-yl)methanone

¹H NMR (500 MHz, CDCl₃) δ 7.96 (s, 1H); 7.81 (d, 2H, J=8.0 Hz); 7.51 (s,1H); 7.41 (t, 2H, J=7.5 Hz); 7.30 (t, 3H, J=7.5 Hz); 6.96 (d as m, 3H,J=8.0 Hz); 4.05 (dt, 1H, J=13.0 Hz, J=4.0 Hz); 3.90-3.82 (m, 1H); 3.77(t, 2H, J=4.0 Hz); 3.56 (dd, 1H, J=26.0.1=14.0 Hz J=5.0 Hz); 3.26 (d asm, 1H, J=12.0 Hz, J=3.5 Hz); 2.90 (dt, 1H, J=13.0 Hz, J=3.0 Hz); 1.06(d, 3H, J=7.0 Hz).

Example 99:((1S,4S)-5-([1,1′-Biphenyl]-3-ylmethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(4-phenyl-1H-imidazol-1-yl)methanone

¹H NMR (500 MHz, CDCl₃) δ 7.89 (d, 1H, J=7.5 Hz); 7.77 (d, 1H, J=2.0Hz); 7.53 (t, 1H, J=8.0 Hz), 7.18 (d, 1H, J=1.0 Hz); 7.06 (t, 1H, J=7.5Hz, J=1.0 Hz); 7.01 (d, 1H, J=8.0 Hz); 3.96 (d, 2H, J=13.0 Hz), 3.54(dt, 2H, J=13.0 Hz, J=2.0 Hz); 2.77 (s, 2H); 2.20 (d, 2H, J=13.0 Hz),1.74 (dt, 2H, J=13.5 Hz, J=5.0 Hz).

Example 100:((1S,4S)-5-([1,1′-Biphenyl]-3-ylmethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(4-bromo-1H-imidazol-1-yl)methanone

¹H NMR (500 MHz, CDCl₃) δ 7.96 (s, 1H); 7.81 (d, 2H, J=8.0 Hz); 7.51 (s,1H); 7.41 (t, 2H, J=7.5 Hz); 7.30 (dt, 1H, J=8.0 Hz, J=2.0 Hz); 7.11 (d,2H, J=8.0 Hz); 6.88 (d, 2H, J=8.0 Hz); 3.96 (dt, 1H, J=13.0 Hz, J=4.5Hz); 3.80 (dd, 1H, J=13.0 Hz, J=2.0 Hz); 3.72-3.6 (m, 3H); 3.18 (qd, 2H,J=13.0, J=3.5 Hz); 2.30 (s, 3H), 1.01 (d, 3H, J=6.0 Hz).

Method M: Synthesis of Phenyl Carbamates 58.

As shown in scheme XIII, phenyl(1S,4,S-5-([1,1′-biphenyl]-3-ylmethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate58 was obtained by reaction of bridged piperazine 50, (scheme XI) withphenyl chloroformate at room temperature

The Following Examples were Prepared by Following Method M

Synthesis of Example 101: phenyl(1S,4S)-5-([1,1′-Biphenyl]-3-ylmethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

To a stirred solution of phenyl chloroformate (0.51 mL, 1.53 mmol,) inmethylene chloride (20 mL) at room temperature was added(1S,4S)-2-([1,1′-biphenyl]-3-ylmethyl)-2,5-diazabicyclo[2.2.1]heptane(50, 0.49 g, 1.34 mmol) and triethylamine (0.45 mL, 2.1 mmol). Theresulting mixture was stirred at room temperature for 2 hours. After thecompletion of reaction, as monitored by TLC, the mixture was dilutedwith water, the aqueous layer was extracted with methylene chloride(2×10 mL), and the combined organic layer was dried over MgSO₄. Thesolvent was removed under reduced pressure to give a crude material,which was purified by column chromatography on silica gel to afford 0.54g of phenyl(1S,4S)-5-([1,1′-biphenyl]-3-ylmethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate58 as white solid.

¹H NMR (500 MHz, CDCl3) δ 7.98 (s, 1H); 7.81 (d, 2H, J=8.0 Hz); 7.53 (s,1H); 7.41 (t, 2H, J=7.5 Hz); 7.34 (dt, 1H, J=8.0 Hz, J=2.0 Hz);7.11-6.92 (m, 5H, J=8.0 Hz); 6.88-6.81 (m, 4H); 3.97 (td, 1H, J=13.0 Hz,J=4.5 Hz); 3.85 (dd, 1H, J=13.0 Hz, J=2.0 Hz); 3.72-3.6 (m, 3H); 3.19(qd, 2H, J=13.0, J=3.5 Hz); 2.30 (s, 3H), 1.03 (d, 3H, J=6.0 Hz).

Testing of Inhibitory Compounds

Certain compounds were tested for their MAGL inhibitory activity, whichis expressed as IC₅₀ values see Table 1. The IC₅₀ is the concentrationof the inhibitor, which results in 50% inhibition of the velocity/rateof 2-AG hydrolysis by FAAH/MAGL. The lower the IC₅₀ values, the higherits inhibitory activity. A detailed description of the methods used totest inhibitory activity of compounds is given below.

Example 102: Preparation of Human MAGL (hMAGL)

Recombinant hexahistidine-tagged human MAGL (hMAGL) was expressed in E.coli cells and purified following our recently reported procedures(Zvonok et al Chem. Biol. (2008) 15: 854-862), (Zvonok et at J. ProteomeRes. (2008) 7: 2158-2164).

Example 103: Preparation of Rat MAGL (rMAGL)

Recombinant rMAGL (rMAGL) was expressed in E. coli cells and purified asdescribed for Hmag, (Zvonok et al Chem. Biol. (2008) 15: 854-862),(Zvonok et al. Proteome Res. (2008) 7: 2158-2164).

Example 104: Fluorescent Assay Protocol for hMAGL

Compound inhibition of hMAGL activity was assessed by a fluorometricassay recently developed in our laboratory (Makriyannis et al WO PatentApplication 2009/117444 A1, (2009) 109 pp.), (Zvonok et al Chem. Biol.(2008) 15: 854-862), (Zvonok et al J. Proteome Res. (2008) 7: 158-2164).This medium throughput assay involved a 96-well plate format in whichhMAGL activity was monitored by the hydrolysis of the substrate7-hydroxy-6-methoxy-4-methylcoumarin ester (AHMMCE) to form thefluorescent product, coumarin. In brief, various concentrations of eachcompound were preincubated with hMAGL (175 ng of total protein in E.coli lysate containing hMAGL) for 15 min at room temperature. Upon theaddition of AHMMCE, the reaction was incubated at 25° C. for 120 min;fluorescence readings were taken every 15 min at 360 nm/460 nm(λexcitation/λemission) using a Synergy HT Plate Reader (Bio-Tek,Winooski, Vt.). Under these incubation conditions, negligiblespontaneous AHMMCE hydrolysis was observed. External standards were usedto convert relative fluorescence units to the amount of 4-methylcoumarinformed. All MAGL assays were performed in triplicate for each inhibitorconcentration, and IC50 values were calculated using Prizm software(GraphPad Software, Inc., San Diego, Calif.).

Example 105: Fluorescent Assay Protocol for rMAGL

Procedure was followed as described for hMAGL.

Example 106: Preparation of Transmembrane Domain-Deleted Rat FAAH (ΔTMrFAAH)

Rat ΔTM FAAH was expressed in E. coli cells and purified using theprocedure disclosed by Patricelli et al. Biochemistry (1998) 37:15177-15187.

Example 107: Preparation of Human FAAH in Fusion with N-Terminal MaltoseBinding Tag (MBPΔTMhFAAH)

Human FAAH without putative transmembrane domain following maltosebinding protein was expressed in E. coli cells using pMALcE4 vectorAlapafuja et al J. Med. Chem. (2012) 55: 10074-89.

Example 108: Fluorescent Assay Protocol for ΔTM Rat FAAH

Procedure was followed as described for hMAGL, except thatarachidonoyl-methyl coumarin amide (AAMCA) was used as fluorigenicsubstrate. Compounds were diluted in 50:50 DMSO/assay buffer (50 mMHEPES, 1 mM EDTA, 0.1% BSA, pH 7.4) so as to have a final DMSOconcentration below 8% in each reaction. For the screening assay, 3concentrations (1 μM, 10 μM, and 100 μM) of test compounds, 15 μg of ΔTMrFAAH and assay buffer were pre-incubated for 15 min at 25° C. AAMCA (20μM, 2×Km) was added prior to incubation at 25° C. and kineticfluorescence reading every 20 minutes (λ_(ex)=360/λ_(em)=460) for 4hours on a BioTek Synergy HT Microplate Reader (BioTek Instruments,Winooski, Vt.). The fluorescence reading at the 3 hour time point(linear enzyme kinetics) was used to calculate percent inhibition basedon control assays without inhibitor present. All FAAH assays wereperformed in triplicate for each inhibitor concentration, and IC₅₀values determined using Prizm software (GraphPad Software, Inc.).

Example 109: Fluorescent Assay Protocol for hFAAH

Procedure was followed as described for rFAAH.

For Table 1 the FAAH/MAGL inhibition as IC₅₀ μM index is as follow:

A=0.01 μM-0.1 μM B=0.11 μM-1.00 μM C=>1.00 μM

TABLE 1 IC₅₀ Examples rFAAH hFAAH rMAGL hMAGL Example 1 A A C C Example2 B C C C Example 3 A A C C Example 4 A A C C Example 5 C C C C Example6 A A B B Example 7 A A C C Example 8 A A C C Example 9 A A C C Example10 A A C C Example 11 A A C C Example 12 A A C C Example 13 A A C CExample 14 C C C C Example 15 C C C C Example 16 C C C C Example 17 A AC C Example 18 A B C C Example 19 B B C C Example 20 B B C C Example 21B B C C Example 22 B B C C Example 23 A B C C Example 24 A B C C Example25 A A C C Example 26 A B C C Example 27 B B C C Example 28 B B C CExample 29 B B C C Example 30 C B C C Example 31 A A C C Example 32 B BC C Example 33 C C C C Example 34 A A C C Example 35 C C C C Example 36A A C C Example 37 A A C C Example 38 B B C C Example 39 B B C C Example40 C C C B Example 41 B B C C Example 42 C C A A Example 43 C C A AExample 44 A A C C Example 45 A A C C Example 46 A A C C Example 47 A AC C Example 48 B A C C Example 49 C C B B Example 50 C C B B Example 51A A C C Example 52 A A B A Example 53 A A A A Example 54 B A B B Example55 A A B A Example 56 B B B B Example 57 C C A A Example 58 C C A AExample 59 B A A A Example 60 B A A A Example 61 A A A C Example 62 A AA C Example 63 C C B B Example 64 C C A A Example 65 C C B B Example 66C C A A Example 67 C C A A Example 68 C C B B Example 69 B B A A Example70 B B B B Example 71 B B A A Example 72 B B B B Example 73 C C A AExample 74 A A C B Example 75 A A C B Example 76 A A B B Example 77 A AB B Example 78 A A C C Example 79 A A B B Example 80 A A C C Example 81B B C C Example 82 B B C C Example 83 A A C C Example 84 A A C C Example85 A A C C Example 86 A A C C Example 87 A A A A Example 88 A A A AExample 89 A A A A Example 90 A A A A Example 91 A A A A Example 74 A AC B Example 75 A A C B Example 76 A A B B Example 77 A A B B Example 78A A C C Example 79 A A B B Example 80 A A C C Example 81 B B C C Example82 B B C C Example 83 A A C C Example 84 A A C C Example 85 A A C CExample 86 A A C C Example 87 A A A A Example 88 A A A A Example 89 A AA A Example 90 A A A A Example 91 A A A A Example 92 C C C C Example 93C C C C Example 94 B B C C Example 95 A A C C Example 96 A A C C Example97 B B C C Example 98 C C C C Example 99 A B C C Example 100 A A C CExample 101 A A C C

Example names and structures are provided below, in Table 2.

Example Name Structure Example 1 (S)-N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-3-methyl-4- (quinolin-2-ylmethyl)piperazine-1-carboxamide

Example 2 (R)-N-(3′-carbamoyl-[1,1′- biphenyl]-3-yl)-3-methyl-4-(quinolin-2-ylmethyl)piperazine- 1-carboxamide

Example 3 (S)-N-(3′-cyano-[1,1′-biphenyl]-3- yl)-2-methyl-4-(3-phenoxybenzyl)piperazine-1- carboxamide

Example 4 (S)-N-(3′-carbamoyl-[1,1′- biphenyl]-3-yl)-2-methyl-4-(3-phenoxybenzyl)piperazine-1- carboxamide

Example 5 (S)-N-(5-(3-cyanophenyl)pyridin- 3-yl)-2-methyl-4-(3-phenoxybenzyl)piperazine-1- carboxamide

Example 6 N-(3′-carbamoyl-[1,1′-biphenyl]- 3-yl)-4-(quinolin-3-ylmethyl)piperazine-1- carboxamide

Example 7 N-(3′-carbamoyl-[1,1′-biphenyl]- 3-yl)-4-phenylpiperazine-1-carboxamide

Example 8 N-(3′-carbamoyl-[1,1′-biphenyl]- 3-yl)-4-(9H-fluoren-9-yl)piperazine-1-carboxamide

Example 9 N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-(pyridin-2-yl)piperazine-1- carboxamide

Example 10 4-([1,1′-biphenyl]-4-ylmethyl)-N-(3′-carbamoyl-[1,1′-biphenyl]-3- yl)piperazine-1-carboxamide

Example 11 N-(3′-carbamoyl-[1,1′-biphenyl]- 3-yl)-4-phenylpiperazine-1-carboxamide

Example 12 N-(3′-carbamoyl-[1,1′-biphenyl]- 3-yl)-4-(quinolin-2-ylmethyl)piperazine-1- carboxamide

Example 13 N-(3′-cyano-[1,1′-biphenyl]-3-yl)- 4-(quinolin-2-ylmethyl)piperazine-1- carboxamide

Example 14 N-(3-phenoxyphenyl)-4-(quinolin- 2-ylmethyl)piperazine-1-carboxamide

Example 15 N-(3′-cyano-[1,1′-biphenyl]-3-yl)-4-phenylpiperidine-1-carboxamide

Example 16 N-(5-(3-cyanophenyl)pyridin-3- yl)-4-phenylpiperidine-1-carboxamide

Example 17 4-([1,1-biphenyl]-3-ylmethyl)-N- (3′-cyano-[1,1′-biphenyl]-3-yl)piperazine-1-carboxamide

Example 18 N-(3′-carbamoyl-[1,1′-biphenyl]- 3-yl)-4-(3-phenoxybenzyl)piperazine-1- carboxamide

Example 19 (S)-N-(3′-cyano-[1,1′-biphenyl]-3-yl)-3-methyl-4-(quinolin-2- ylmethyl)piperazine-1- carboxamide

Example 20 N-(3′-cyano-[1,1′-biphenyl]-3-yl)- 4-oxospiro[chromane-2,4′-piperidine]-1′-carboxamide

Example 21 (S)-(4-([1,1′-biphenyl]-3- ylmethyl)-3-methylpiperazin-1-yl)(4-phenyl-1H-imidazol-1- yl)methanone

Example 22 (S)-(4-bromo-1H-imidazol-1- yl)(2-methyl-4-(3-phenoxybenzyl)piperazin-1- yl)methanone

Example 23 (2-methyl-4-phenylpiperazin-1- yl)(4-phenyl-1H-imidazol-1-yl)methanone

Example 24 (3-methyl-4-phenylpiperazin-1- yl)(4-phenyl-1H-imidazol-1-yl)methanone

Example 25 (3-methyl-4-(p-tolyl)piperazin-1- yl)(4-phenyl-1H-imidazol-1-yl)methanone

Example 26 (4-(3-(benzyloxy)phenyl)-3- methylpiperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone

Example 27 (4-(3-hydroxyphenyl)-3- methylpiperazin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone

Example 28 (4-(bis(4- fluorophenyl)methyl)piperazin-1-yl)(4-bromo-1H-imidazol-1- yl)methanone

Example 29 (4-(bis(4- fluorophenyl)methyl)piperazin-1-yl)(4-phenyl-1H-imidazol-1- yl)methanone

Example 30 (4-benzhydrylpiperazin-1-yl)(4- phenyl-1H-imidazol-1-yl)methanone

Example 31 (4-benzhydrylpiperazin-1-yl)(5- benzyl-1H-tetrazol-1-yl)methanone

Example 32 (5-benzyl-1H-tetrazol-1-yl)(4- (bis(4-fluorophenyl)methyl)piperazin-1- yl)methanone

Example 33 (3-(Carbomethoxy)-1H-1,2,4- triazol-1-yl)(4-(bis(4-fluorophenyl)methyoxy) piperidin-1-yl)methanone

Example 34 4′-(4-bromo-1H-imidazole-1- carbonyl)spiro[chromane-2,1′-cyclohexan]-4-one

Example 35 3-Cyanophenyl 4-(2-methyl-1- phenylpropyl)piperazine-1-carboxylate

Example 36 3-cyanophenyl 4-(1- phenylethyl)piperazine-1- carboxylate

Example 37 3-cyanophenyl 4- (cyclopentyl(phenyl)methyl)piperazine-1-carboxylate

Example 38 3-cyano-5-hydroxyphenyl 4- benzhydrylpiperazine-1-carboxylate

Example 39 6-chloropyridin-2-yl 4- benzhydrylpiperazine-1- carboxylate

Example 40 3-cyanophenyl 4-(bis(4- fluorophenyl)methyl)piperazine-1-carboxylate

Example 41 3-cyanophenyl 4-(9H-fluoren-9- yl)piperazine-1-carboxylate

Example 42 4-cyanopyridin-2-yl 4-(9H- fluoren-9-yl)piperazine-1-carboxylate

Example 43 3-cyanopyridin-2-yl 4-(9H- fluoren-9-yl)piperazine-1-carboxylate

Example 44 3-Cyanophenyl 4-benzhydryl piperazine-1-carboxylate

Example 45 5-Cyano-2-fluorophenyl 4- benzylpiperidine-1-carboxylate

Example 46 3-Cyanophenyl 4- benzhydrylpiperidine-1- carboxylate

Example 47 3-cyanophenyl 4- (diphenylmethylene)piperidine-1- carboxylate

Example 48 3-(methoxycarbonyl)phenyl 4- (diphenylmethylene)piperidine-1-carboxylate

Example 49 5-cyano-2-fluorophenyl 4- benzhydrylpiperidine-1- carboxylate

Example 50 3-cyano-5-hydroxyphenyl 4- benzhydrylpiperidine-1-carboxylate

Example 51 6-Chloropyridin-2-yl 4- (benzhydryl)piperidine-1- carboxylate

Example 52 3-cyanophenyl 4- benzylpiperidine-1-carboxylate

Example 53 3-cyanophenyl 4-((4- chlorophenyl)(2-chloropyridin-3-yl)methoxy)piperidine-1- carboxylate

Example 54 6-Chloropyridin-2-yl 4- (benzhydryl)piperidine-1- carboxylate

Example 55 3-(methoxycarbonyl)phenyl 4- (benzhydryloxy)piperidine-1-carboxylate

Example 56 5-cyano-2-fluorophenyl 4- (benzhydryloxy)piperidine-1-carboxylate

Example 57 6-chloropyridin-2-yl 4- (benzhydryloxy)piperidine-1-carboxylate

Example 58 3-cyanophenyl 4- (benzhydryloxy)piperidine-1- carboxylate

Example 59 3-Cyanophenyl 4-(4- bromophenylsulfonyl)piperidine-1-carboxylate

Example 60 5-Cyano-2-fluorophenyl 4-(4- bromophenylsulfonyl)piperidine-1-carboxylate

Example 61 5-Cyano-2-methylphenyl 4-(4- bromophenylsulfonyl)piperidine-1-carboxylate

Example 62 5-Cyano-2-methoxyphenyl 4-(4- bromophenylsulfonyl)piperidine-1-carboxylate

Example 63 2,6-Difluorophenyl 4-(4- bromophenylsulfonyl)piperidine-1-carboxylate

Example 64 4-bromophenyl 4-tosylpiperazine- 1-carboxylate

Example 65 2,6-difluorophenyl 4- tosylpiperazine-1-carboxylate

Example 66 4′-fluoro-3-hydroxy-[1,1′- biphenyl]-4-yl 4-tosylpiperazine-1-carboxylate

Example 67 N-(3-(1,1- dioxidothiomorpholino)phenyl)-4-phenylpiperazine-1-carboxamide

Example 68 N-(3-(1,1- dioxidothiomorpholino)phenyl)-4-phenylpiperidine-1-carboxamide

Example 69 3-(1,1- dioxidothiomorpholino)phenyl 4-phenylpiperazine-1-carboxylate

Example 70 3-(1,1-Dioxothiomorpholin-4- yl)phenyl 4-phenylpiperidine-1-carboxylate

Example 71 3-(1,1- dioxidothiomorpholino)phenyl 4-(3-phenoxybenzyl)piperazine-1- carboxylate

Example 72 3-(1,1- dioxidothiomorpholino)phenyl 4-(quinolin-2-ylmethyl)piperazine- 1-carboxylate

Example 73 3-(1,1- dioxidothiomorpholino)phenyl 2-methyl-4-phenylpiperazine-1- carboxylate

Example 74 3-Cyanophenyl 3-(4- chlorobenzyloxy)azetidine-1- carboxylate

Example 75 3-(Trifluoromethyl)phenyl 3-(4- chlorobenzyloxy)azetidine-1-carboxylate

Example 76 3-Bromophenyl 3-(4- chlorobenzyloxy)azetidine-1- carboxylate

Example 77 3-Carbamoylphenyl 3-(4- chlorobenzyloxy)azetidine-1-carboxylate

Example 78 3-Methoxyphenyl 3-(4- Bromobenzyloxy)azetidine-1- carboxylate

Example 79 2,4-Dichlorophenyl 3-(4- chlorobenzyloxy)azetidine-1-carboxylate

Example 80 3-(Pyridin-3-yl)phenyl 3-(4- chlorobenzyloxy)azetidine-1-carboxylate

Example 81 3-(4-Chlorobenzyloxy)-N- phenylazetidine-1-carboxamide

Example 82 3-(4-Bromobenzyloxy)-N- (pyridin-3-yl)azetidine-1-carboxamide

Example 83 (1H-Benzo[d]imidazol-1-yl)(3-(4-phenylpiperidin-1-yl)azetidin-1- yl)methanone

Example 84 (3-(4-Benzylpiperidine)azetidin-1-yl)(4-phenyl[1H]imidazol-1- yl)methanone

Example 85 (4-Phenyl-1H-imidazol-1-yl)(3-(4-phenylpiperidin-1-yl)azetidin-1- yl)methanone

Example 86 (3-(4-Bromobenzyloxy)azetidin-1- yl)(4-phenyl-1H-imidazol-1-yl)methanone

Example 87 (1H-Benzo[d]imidazol-1-yl)(3-(4- Bromobenzyloxy)azetidin-1-yl)methanone

Example 88 3-(4-Bromobenzyloxy)azetidin-1- yl](piperidin-1-yl)methanone

Example 89 (3-(4-Phenylpiperidin-1- yl)azetidin-1-yl)(1H-pyrazol-1-yl)methanone

Example 90 3-(4-Phenylpiperidin-1- yl)azetidin-1-yl)(1H-1,2,4-triazol-1-yl)methanone

Example 91 3-(4-Bromphenylthio)azetidin-1- yl)(1H-1,2,4-triazol-1-yl)methanone

Example 92 (1S,4S)-N-(3′-carbamoyl-[1,1′- biphenyl]-3-yl)-5-(quinolin-2-ylmethyl)-2,5- diazabicyclo[2.2.1]heptane-2- carboxamide

Example 93 (1S,4S)-N-(3′-cyano-[1,1′- biphenyl]-3-yl)-5-(quinolin-2-ylmethyl)-2,5- diazabicyclo[2.2.1]heptane-2- carboxamide

Example 94 (1S,4S)-5-([1,1′-biphenyl]-3- ylmethyl)-N-(3′-cyano-[1,1′-biphenyl]-3-yl)-2,5- diazabicyclo[2.2.1]heptane-2- carboxamide

Example 95 (1S,4S)-N-(3-bromophenyl)-5- (quinolin-2-ylmethyl)-2,5-diazabicyclo[2.2.1]heptane-2- carboxamide

Example 96 (4-phenyl-1H-imidazol-1- yl)((1S,4S)-5-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2- yl)methanone

Example 97 ((1S,4S)-5-(3-fluorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(4- phenyl-1H-imidazol-1- yl)methanone

Example 98 ((1S,4S)-5-(3-(benzyloxy)phenyl)-2,5-diazabicyclo[2.2.1]heptan-2- yl)(4-phenyl-1H-imidazol-1-yl)methanone

Example 99 ((1S,4S)-5-([1,1′-biphenyl]-3- ylmethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(4- phenyl-1H-imidazol-1- yl)methanone

Example 100 ((1S,4S)-5-([1,1′-biphenyl]-3- ylmethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(4- bromo-1H-imidazol-1- yl)methanone

Example 101 phenyl (1S,4S)-5-([1,1′-biphenyl]- 3-ylmethyl)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate

We have studied compounds of Example 1, 7, 46, and 52 in vivo.

Compounds 1, 7, and 52 were examined for blood-brain distributionparameters according to the assay described below.

Example 110: Blood Brain Barrier (BBB) Permeability Studies

Novel compounds were studied for their abilities to cross the bloodbrain barrier based on procedures adapted from Cluny, et al (2010),British journal of pharmacology 161: 629; Rahn, et al (2011)Pharmacology biochemistry, and behavior 98: 493; Wood et al (2013) Lifesciences 92: 482.

For example, compounds 1, 7, and 52 have brain/plasma ratio of 0.03,0.17 and 0.71, respectively.

Example 111: Anticipatory Nausea Studies

Novel compounds were studied for their ability to ameliorateLiCl-induced anticipatory nausea in rats following the proceduresdescribed in Limebeer, C. L. et al Psychopharmacology (2014)231:603-612. For example compounds 46 (20 mg/Kg) and 52 (20 mg/Kg)ameliorated anticipatory nausea in rats. Mean number of gapes elicitedby a LiCl-paired context in an anticipatory nausea test followingpretreatment with a MAGL inhibitor compound 46 and dual FAAH/MAGLinhibitor 52 were 8 and 3 respectively, compared to animals treated withvehicle which show 22 gapes.

Example 112: Xenograft Model of Advanced Prostate Cancer

Compounds were studied for their abilities to retard tumor growth inmouse xenograft model expressing aggressive human prostate cancer PC-3Mcells. Tumors were established in immunodeficient nude mice (TaconicFarms) according to standard protocol and mice were divided in twogroups. Mouse in each group was injected intraperitoneally (i.p.) withvehicle or compounds (20 mg/kg daily) for 21 days. Tumor sizes weremeasured with callipers every 3 days. For example, animals treated withcompound 46 showed a 43% reduction in tumor sizes (105 mm³) compared toanimals treated with vehicle (185 mm³).

As will be apparent to one of ordinary skill in the art from a readingof this disclosure, the disclosed subject matter can be embodied informs other than those specifically disclosed above. The particularembodiments described above are, therefore, to be considered asillustrative and not restrictive. Those skilled in the art willrecognize, or be able to ascertain, using no more than routineexperimentation, numerous equivalents to the specific embodimentsdescribed herein. The scope of the invention is as set forth in theappended claims and equivalents thereof, rather than being limited tothe examples contained in the foregoing description.

What is claimed is:
 1. A method for the treatment of a disease ordisorder associated with FAAH, MAGL or dual FAAH/MAGL inhibition in apatient in need thereof, comprising providing to the patient atherapeutically effective amount of a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein: M=O, S; Z=O, NH,or none; and when Z=none, B₂ is directly attached to C=M; n=1-2; L₂ isselected from

—O—, —CH═CH—, —CONH—,

—S—, —S(O)—, SO₂, or —NH—, n=0-2; A₂ is selected from aryl, heteroaryl,fluoren-9-yl, aryl(alkyl)methyl, aryl(cycloalkyl)methyl,heteroaryl(alkyl)methyl, or heteroaryl(cycloalkyl)methyl, and each aryl,heteroaryl or fluoren-9-yl group may be unsubstituted, or substitutedwith one or two moieties selected from: —OH, -alkyl, —O-alkyl, -halogen,—CF₃, —OCF₃, —S— alkyl, —OPh, -Ph, —S(O)-alkyl, —SO₂-alkyl, —CO₂-alkyl,—COOH, —NHR₃, —NR₃R₄, NR₃SO₂R₄, —NO₂, —CN, —CONR₃R₄, -alkynyl,morpholino, thiomorpholino, 1,1-dioxothiomorpholine, or1-oxothiomorpholino; R₃ and R₄ are independently selected from —H,-alkyl, or cycloalkyl; B₂ is selected from aryl or heteroaryl, and eacharyl or heteroaryl may be unsubstituted or substituted with one or twomoieties selected from -halogen, —NO₂, —CN, —OH, —NH₂, —CONH₂, —O-aryl,—CF₃, —OCF₃, —OCF₂H, or —SCF₃; or B₂ is selected from:

wherein: W₁ is CH or N; W₂ is selected from CH₂, O, SO₂, CHAr, or NAr;Ar can be aryl or heteroaryl containing 1 to 3 heteroatoms; R₅ isselected from —H, -halogen, —NO₂, —CN, —OH, -Ph, —COOMe, —NH₂, —CONH₂,—O-aryl, —CF₃, —OCF₃, —OCF₂H, or —SCF₃; R₆ is a monocyclic heteroarylring containing 1 to 3 heteroatoms, and the heteroaryl ring can besubstituted with one or two groups selected from —CN, —OH, —OMe, —CF₃,—OCF₃, —OBn, —CONH₂, —SO₂NH₂, —COOH, -halogen,

wherein M is selected from O or S.
 2. The method according to claim 1,wherein the disease or disorder is selected from the group consisting ofdiabetic neuropathy, anticipatory nausea, THC-dependence,neuroprotection and advanced prostate cancer.
 3. The method according toclaim 1, wherein the disease or disorder is neuropathy.
 4. The methodaccording to claim 1, wherein the disease or disorder is Alzheimer'sdisease.
 5. The method according to claim 1, wherein L₂ is selected from

—O—, —CH═CH—, —CONH—,

—S—, —S(O)—, SO₂, or —NH—, n=0-1.
 6. The method according to claim 1,wherein: M=O; A₂ is selected from aryl or heteroaryl, and each aryl orheteroaryl may be unsubstituted, or substituted with one or two-halogen; B₂ is selected from aryl or heteroaryl, and each aryl orheteroaryl may be unsubstituted or substituted with one or two moietiesselected from -halogen, —CN, —CONH₂, or —CF₃; or B₂ is selected from:

wherein: W₁ is CH or N; W₂ is selected from CH₂, O, SO₂, CHAr, or NAr;Ar can be aryl or heteroaryl containing 1 to 3 heteroatoms; R₅ isselected from —H, -Ph or —COOMe; R₆ is a monocyclic heteroaryl ringcontaining 1 to 3 heteroatoms, and the heteroaryl ring can besubstituted with one or two -halogen.
 7. The method according to claim1, wherein the compound is selected from the group consisting of:3-Cyanophenyl 3-(4-chlorobenzyloxy)azetidine-1-carboxylate;3-(Trifluoromethyl)phenyl 3-(4-chlorobenzyloxy)azetidine-1-carboxylate;3-Bromophenyl 3-(4-chlorobenzyloxy)azetidine-1-carboxylate;3-Carbamoylphenyl 3-(4-chlorobenzyloxy)azetidine-1-carboxylate;3-Methoxyphenyl 3-(4-bromobenzyloxy)azetidine-1-carboxylate;2,4-Dichlorophenyl 3-(4-chlorobenzyloxy)azetidine-1-carboxylate;3-(Pyridin-3-yl)phenyl 3-(4-chlorobenzyloxy)azetidine-1-carboxylate;3-(4-Chlorobenzyloxy)-N-phenylazetidine-1-carboxamide;3-(4-Bromobenzyloxy)-N-(pyridin-3-yl)azetidine-1-carboxamide;(1H-Benzo[d]imidazol-1-yl)(3-(4-phenylpiperidin-1-yl)azetidin-1-yl)methanone;(3-(4-Benzylpiperidine)azetidin-1-yl)(4-phenyl[1H]imizadol-1-yl)methanone;(4-Phenyl-1H-imidazol-1-yl)(3-(4-phenylpiperidin-1-yl)azetidin-1-yl)methanone;(3-(4-Bromobenzyloxy)azetidin-1-yl)(4-phenyl-1H-imidazol-1-yl)methanone;(1H-Benzo[d]imidazol-1-yl)(3-(4-bromobenzyloxy)azetidin-1-yl)methanone;3-(4-Bromobenzyloxy)azetidin-1-yl](piperidin-1-yl)methanone;(3-(4-Phenylpiperidin-1-yl)azetidin-1-yl)(1H-pyrazol-1-yl)methanone;3-(4-Phenylpiperidin-1-yl)azetidin-1-yl)(1H-1,2,4-triazol-1-yl)methanone;and 3-(4-Bromophenylthio)azetidin-1-yl)(1H-1,2,4-triazol-1-yl)methanone,or a pharmaceutically acceptable salt of any of the foregoing.
 8. Themethod according to claim 1, wherein the compound is 3-cyanophenyl3-(4-chlorobenzyloxy)azetidine-1-carboxylate, or a pharmaceuticallyacceptable salt thereof.
 9. The method according to claim 1, wherein thecompound is(1H-benzo[d]imidazol-1-yl)(3-(4-bromobenzyloxy)azetidin-1-yl)methanone,or a pharmaceutically acceptable salt thereof.
 10. A compound of formulaIA:

or a pharmaceutically acceptable salt thereof, wherein: X=CH, N; R₁=—H,-alkyl; R₂=—H, -alkyl, where alkyl is saturated C₁₋₁₀ hydrocarbon, whichmay be straight or branched chain; n=0-3; A₁ is selected from aryl,heteroaryl, benzhydryl, fluorenyl, aryl(aryl)methyl, aryl(phenyl)methyl,aryl(alkyl)methyl, or aryl(cycloalkyl)methyl, and each aryl, heteroarylor fluorenyl group may be unsubstituted, or mono or di-substituted withthe following moieties: —NO₂, —CN, —OH, -alkyl, —O-alkyl, -halogen,—CF₃, —OCF₃, —S— alkyl, —OPh, -Ph —S(O)-alkyl, —SO₂-alkyl, —CO₂-alkyl,—COOH, —NHR₃, —NR₃R₄, —NR₃SO₂R₄, —NO₂, —CN, —CONR₃R₄, morpholino,thiomorpholino, 1,1-dioxothiomorpholine, or oxothiomorpholino; R₃ and R₄are independently selected from —H, -alkyl, or cycloalkyl; and R₆ isselected from H, —CN, —OH, —OMe, —CF₃, —OCF₃, —OBn, —CONH₂, —SO₂NH₂, or—COOH.
 11. The compound according to claim 10, wherein X=N and n=0-1.12. The compound according to claim 10, wherein R₆ is selected from —H,—CN, —CONH₂, or —CF₃.
 13. The compound according to claim 10, wherein A₁is selected from the group consisting of phenoxyphenyl, quinolinyl,phenyl, fluorenyl, pyridinyl and biphenyl.
 14. The compound according toclaim 10, wherein the compound is selected from the group consisting of:(S)—N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-3-methyl-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide;(S)—N-(3′-cyano-[1,1′-biphenyl]-3-yl)-2-methyl-4-(3-phenoxybenzyl)piperazine-1-carboxamide;(S)—N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-2-methyl-4-(3-phenoxybenzyl)piperazine-1-carboxamide;N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-(quinolin-3-ylmethyl)piperazine-1-carboxamide;N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-phenylpiperidine-1-carboxamide;N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-(9H-fluoren-9-yl)piperazine-1-carboxamide;N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-(pyridin-2-yl)piperazine-1-carboxamide;4-([1,1′-biphenyl]-4-ylmethyl)-N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)piperazine-1-carboxamide;N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-phenylpiperazine-1-carboxamide;N-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide;N-(3′-cyano-[1,1′-biphenyl]-3-yl)-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide;4-([1,1′-biphenyl]-3-ylmethyl)-N-(3′-cyano-[1,1′-biphenyl]-3-yl)piperazine-1-carboxamide;andN-(3′-carbamoyl-[1,1′-biphenyl]-3-yl)-4-(3-phenoxybenzyl)piperazine-1-carboxamide,or a pharmaceutically acceptable salt of any of the foregoing.
 15. Acompound of formula IB:

or a pharmaceutically acceptable salt thereof, wherein: R₁=—H, -alkyl;R₂=—H, -alkyl, where alkyl is saturated C₁₋₁₀ hydrocarbon, which may bestraight or branched chain; L₁ is selected from a double bond,—(CH₂)_(n), —O—, —CH═CH—, —CONH—, —S—, —S(═O)—, SO₂, —NH—, or —NR₁,where n=0-6; A₁ is selected from aryl, heteroaryl, benzhydryl,fluorenyl, aryl(aryl)methyl, aryl(phenyl)methyl, aryl(alkyl)methyl,aryl(cycloalkyl)methyl and each aryl, heteroaryl or fluorenyl group maybe unsubstituted, or mono or di-substituted with the following moieties:—NO₂, —CN, —OH, -alkyl, —O-alkyl, -halogen, —CF₃, —OCF₃, —S— alkyl,—OPh, -Ph —S(O)-alkyl, —SO₂-alkyl, —CO₂-alkyl, —COOH, —NHR₃, —NR₃R₄,—NR₃SO₂R₄, —NO₂, —CN, —CONR₃R₄, morpholino, thiomorpholino,1,1-dioxothiomorpholine or oxothiomorpholino; R₃ and R₄ areindependently selected from —H, -alkyl, or cycloalkyl; R₅ is selectedfrom H, OH, or halogen; and R₆ is selected from H, —CN, —OH, —OMe, —CF₃,—OCF₃, —OBn, —CONH₂, —SO₂NH₂ or —COOH.
 16. The compound according toclaim 15, wherein L₁ is selected from a double bond or —(CH₂)_(n), wheren=0-1.
 17. The compound according to claim 15, wherein R₅ is selectedfrom H or halogen; and R₆ is selected from —H, —CN, —CONH₂, or —CF₃. 18.The compound according to claim 15, wherein A₁ is selected from thegroup consisting of phenyl and benzhydryl.
 19. The compound according toclaim 15, wherein the compound is selected from the group consisting of:5-Cyano-2-fluorophenyl 4-benzylpiperidine-1-carboxylate; 3-Cyanophenyl4-benzhydrylpiperidine-1-carboxylate; 3-Cyanophenyl4-(diphenylmethylene)piperidine-1-carboxylate; and 3-Cyanophenyl4-benzylpiperidine-1-carboxylate, or a pharmaceutically acceptable saltof any of the foregoing.